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Metabolism, Clinical and Experimental: seventy years young and growing

  • Author Footnotes
    1 These authors contributed equally to this article.
    Stergios A. Polyzos
    Footnotes
    1 These authors contributed equally to this article.
    Affiliations
    First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
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  • Author Footnotes
    1 These authors contributed equally to this article.
    Michael A. Hill
    Footnotes
    1 These authors contributed equally to this article.
    Affiliations
    Dalton Cardiovascular Research Center, Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
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  • Ghada El-Hajj Fuleihan
    Affiliations
    Division of Endocrinology, Calcium Metabolism and Osteoporosis Program, World Health Organization Collaborating Center for Metabolic Bone Disorders, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
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  • Luigi Gnudi
    Affiliations
    School of Cardiovascular and Metabolic Medicine & Sciences, King's College, London, UK
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  • Young-Bum Kim
    Affiliations
    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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  • Susanna C. Larsson
    Affiliations
    Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

    Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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  • Hiroaki Masuzaki
    Affiliations
    Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology, Second Department of Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
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  • Giuseppe Matarese
    Affiliations
    Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli “Federico II”, Naples, Italy

    Laboratorio di Immunogenetica dei Trapianti & Registro Regionale dei Trapianti di Midollo, AOU "Federico II”, Naples, Italy

    Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale Consiglio Nazionale delle Ricerche, Naples, Italy
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  • Despina Sanoudou
    Affiliations
    Clinical Genomics and Pharmacogenomics Unit, 4th Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

    Biomedical Research Foundation of the Academy of Athens, Athens, Greece

    Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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  • Manuel Tena-Sempere
    Affiliations
    Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), Cordoba, Spain

    Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain
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  • Christos S. Mantzoros
    Correspondence
    Corresponding author at: Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA.
    Affiliations
    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
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  • Author Footnotes
    1 These authors contributed equally to this article.
Published:October 13, 2022DOI:https://doi.org/10.1016/j.metabol.2022.155333

      Keywords

      Abbreviations:

      25OHD (25-hydroxy-vitamin D)

      Abbreviations

      AIS
      Article Influence Score
      AMPK
      AMP-activated kinase
      APC
      article processing charge
      BAT
      brown adipose tissue
      BCAA
      branched chain amino acid
      BCKA
      branched chain ketoacid
      BMI
      body mass index
      BMP
      bone morphogenetic protein
      CAP
      casitas B-lineage lymphoma protein-associated protein
      CCL
      C-C chemokine ligand
      CKD
      chronic kidney disease
      CXCR
      CXC chemokine receptors
      DC
      dendritic cell
      EES
      Elsevier Editorial System
      ER
      endoplasmic reticulum
      ERK
      extracellular signal-regulated kinase
      F
      fibrosis stage
      FNDC
      fibronectin type III domain-containing protein
      GLP-1RA
      glucagon-like peptide-1 receptor agonist
      GnRH
      gonadotropin-releasing hormone
      GRK
      G-protein coupled receptor kinase
      HIT
      high-intensity interval training
      HCC
      hepatocellular carcinoma
      IL
      interleukin
      IDE
      insulin-degrading enzyme
      IRE1α
      inositol-requiring enzyme 1 alpha
      KO
      knockout
      LPS
      lipopolysaccharide
      LYN
      Lck/Yes-related novel protein
      MAFLD
      metabolic dysfunction-associated fatty liver disease
      MSCs
      mesenchymal stem cells
      MC4R
      melanocortin 4 receptor
      MST
      mammalian serine/threonine-protein kinase
      NAFLD
      nonalcoholic fatty liver disease
      NASH
      nonalcoholic steatohepatitis
      NHANES
      National Health and Nutrition Examination Survey
      NK
      natural killer
      NKG2DL
      NK group 2, member D ligand
      NLRP
      Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing
      PPAR
      peroxisome proliferator-activated receptor
      PCOS
      polycystic ovary syndrome
      PD-L
      programmed death-ligand
      PWV
      pulse wave velocity
      rHDL-apoE3
      reconstituted HDL-apolipoproteinE3
      RCT
      randomized controlled trial
      SGLT
      sodium-glucose cotransporter
      SJR
      SCImago journal rank
      SKA
      Small conductance K-channel Activators
      SPRY
      Sprouty
      Q
      quartile
      T2DM
      type 2 diabetes mellitus
      TGF
      transforming growth factor
      TNF
      tumor necrosis factor
      Wnt
      wingless, WT, wild type

      1. Metabolism”: its history in brief

      Metabolism: Clinical and Experimental”, initially published by Grune & Stratton Inc. (New York) in 1952 [
      • Soskin S.
      Editorial: resignation of editor-in-chief.
      ] and acquired by Elsevier in 2002, celebrates its 70th anniversary in 2022. Dr. Samuel Soskin, the founding Editor-in-Chief, was succeeded by Dr. Garfield G. Duncan in 1958 [
      • Duncan G.G.
      Editorial.
      ], then by Dr. James B. Fields in 1970 [
      • Field J.B.
      Editorial.
      ], who served for over 40 years [
      • Field J.B.
      Passing the torch.
      ], and then by Dr. Christos S. Mantzoros in 2010 as current Editor-in-Chief [
      • Mantzoros C.S.
      Accepting the torch.
      ]. The Editorial Board of “Metabolism” (www.journals.elsevier.com/metabolism/editorial-board) currently consists of 10 Associate Editors and 72 Editorial Board Members, men and women, younger and more experienced, from 20 countries around the world.
      Since inception, “Metabolism” has strived to connect investigators with practicing physicians, by publishing high quality basic, translational and clinical research that demonstrates substantial scientific and clinical implications. By 1970, “Metabolism” was indeed a successful journal; leaders in the field contributed their articles to “Metabolism” and there was a progressive increase in subscriptions [
      • Field J.B.
      Editorial.
      ,
      • Duncan G.G.
      An adieu.
      ]. A definite turning point for the journal was the transition to electronic submission in the 2000s, initially via the Elsevier Editorial System (EES) and currently by Editorial Manager (www.editorialmanager.com/metabolism) [
      • Miller A.
      • Fain J.N.
      • Bray G.A.
      Tributes to retiring editor-in-chief of metabolism, James B. Field.
      ]. This has facilitated the editorial process, reducing the time to first decision and time to publication [
      • Field J.B.
      Passing the torch.
      ] and leading to accepted articles and new ideas being more rapidly disseminated.
      Metabolism” has its own website (www.journals.elsevier.com/metabolism), but its articles are also available, early after their acceptance and before being published in print, through ScienceDirect (www.sciencedirect.com) and most international databases, in which it is indexed. “Metabolism” follows a hybrid model of publication, i.e., the authors may select to publish their articles free of charge by transferring the copyright to ELSEVIER or pay an article processing charge (APC), thus retaining the copyright and publishing their articles under Open Access, making them freely available. At the discretion of Editor-in-Chief selected innovative and meritorious articles are chosen each year to be highlighted as freely available, without the need of an APC.
      During the last years, “Metabolism” has shown quite a dramatic improvement in its metrics, which likely reflects both the quality of the published articles and the editorial process. The trends in the metrics can be monitored online in detail through established agencies including Clarivate, Scopus and Scimago Lab. The latest impact factor for “Metabolism” (2021) is 13.934, which ranks the journal at the 7th position (Q1 quartile; 96th percentile) out of 146 journals in the category of “Endocrinology & Metabolism” (Clarivate; Fig. 1A ). Other established metrics show a similar pattern: the 5-year impact factor is currently 10.859, ranking Metabolism at the 10th position (Q1 quartile) out of 146 journals in the category of “Endocrinology & Metabolism” (Clarivate; Fig. 1B); CiteScore (2021) is 16.5 (16.8 on September 5, 2022), ranking “Metabolism” at the 5th position (98th percentile, September 5, 2022) out of 227 journals in the category of “Endocrinology, Diabetes and Metabolism” (Scopus; Fig. 1C). Article Influence Score (AIS) and SCImago journal rank (SJR), which are more complex metrics, for which the citations received are weighted for the publication source they are derived from [
      • Polyzos S.A.
      • Mantzoros C.S.
      Sixty-six years of metabolism, clinical and experimental: the journey of a journal and opportunities and challenges looking ahead.
      ], progressively increased from 0.770 in 2007 to 2.416 in 2021, and from 0.789 in 1999 to 2.733 in 2021, respectively. The number of paper downloads has also increased significantly over the same period. Collectively, these metrics indicate that Metabolism is widely perceived as a high-quality journal and that this can be appreciated as such by authors, readers and the editorial staff. Recent, independently run, author surveys provide data indicating almost 100 % satisfaction with both the editorial team and the journal overall, a metric that stands out in comparison to all other journals in the same field.
      Fig. 1
      Fig. 1A. The impact factor of “Metabolism” during the period 1997–2021 (source: Clarivate; 2022).
      B. The 5-year impact factor of “Metabolism” during the period 2007–2021 (source: Clarivate; 2022).
      C. The CiteScore of “Metabolism” during the period 2011–2021 (source: Scopus; 2022).
      Despite this apparent success story of continuous improvement over the past 12 years, the vision and mission of the editors of “Metabolism” stays unmoved today, 70 years after its first circulation. “Metabolism” continues to “promote excellence in research by publishing high-quality clinical and experimental articles relevant to all aspects of human metabolism”, as stated in the scope of the journal (www.journals.elsevier.com/metabolism). Furthermore, “Metabolism” has never altered its aim to interconnect researchers and physicians with contemporary scientific knowledge and to convert science into clinical practice. Thus, in the current context, "Metabolism" strives to be a journal of "translational" relevance. We hereby would like to acknowledge the continuous efforts of the authors, reviewers and editors of the journal that have supported and continue to support its upward trend in the literature and science, sometimes under certain sociopolitical and scientific challenges, which make the journey even more challenging. We would also like to thank the numerous readers of “Metabolism”, who are always at the center of our efforts and keep the journal alive with their interest in the articles of the journal and the never-ending constructive feedback they offer to the journal. The desire for such feedback and discussion will continue to be encouraged through submissions of ‘Letters to the Editor’ and ‘Opinion pieces’ in an effort to further improve the journal and promote scientific dialogue.
      The recent scientific bloom, which “Metabolism” has been experiencing, came as the result of all the above: hard work, consistency and efficiency to provide, through a rigorous review process that both screens and improves papers to be published, state-of-the art scientific progress to the international scientific community for the sake of improving human life and well-being. Thus, we at “Metabolism” align with what Hippocrates quoted over 2000 years ago: “wherever the art of medicine is loved, there is also a love of humanity”.

      2. The most cited review and original articles of the last five years

      The four most cited reviews [
      • Chooi Y.C.
      • Ding C.
      • Magkos F.
      The epidemiology of obesity.
      ,
      • Avgerinos K.I.
      • Spyrou N.
      • Mantzoros C.S.
      • Dalamaga M.
      Obesity and cancer risk: emerging biological mechanisms and perspectives.
      ,
      • Polyzos S.A.
      • Kountouras J.
      • Mantzoros C.S.
      Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics.
      ,
      • Koliaki C.
      • Liatis S.
      • Kokkinos A.
      Obesity and cardiovascular disease: revisiting an old relationship.
      ] and original articles [
      • Palaiodimos L.
      • Kokkinidis D.G.
      • Li W.
      • Karamanis D.
      • Ognibene J.
      • Arora S.
      Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York.
      ,
      • Chen X.
      • Li X.
      • Zhang W.
      • He J.
      • Xu B.
      • Lei B.
      • et al.
      Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-κB pathway.
      ,
      • Watanabe M.
      • Caruso D.
      • Tuccinardi D.
      • Risi R.
      • Zerunian M.
      • Polici M.
      • et al.
      Visceral fat shows the strongest association with the need of intensive care in patients with COVID-19.
      ,
      • Petersen A.
      • Bressem K.
      • Albrecht J.
      • Thieß H.M.
      • Vahldiek J.
      • Hamm B.
      • et al.
      The role of visceral adiposity in the severity of COVID-19: highlights from a unicenter cross-sectional pilot study in Germany.
      ] of “Metabolism” published during the last five years (2018–2022) according to Scopus (www.scopus.com; last update: October 4, 2022) are presented in Table 1, Table 2, respectively. Chooi et al. provided a masterful overview of the epidemiology of obesity [
      • Chooi Y.C.
      • Ding C.
      • Magkos F.
      The epidemiology of obesity.
      ]. Avgerinos et al. summarized pathogenic mechanisms linking obesity with cancer, thus providing therapeutic implications [
      • Avgerinos K.I.
      • Spyrou N.
      • Mantzoros C.S.
      • Dalamaga M.
      Obesity and cancer risk: emerging biological mechanisms and perspectives.
      ]. Polyzos et al. summarized data linking obesity with nonalcoholic fatty liver disease (NAFLD), starting from epidemiology and ending by considering therapeutic perspectives [
      • Polyzos S.A.
      • Kountouras J.
      • Mantzoros C.S.
      Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics.
      ]. Coliaki et al. updated data on the association between obesity and cardiovascular risk [
      • Koliaki C.
      • Liatis S.
      • Kokkinos A.
      Obesity and cardiovascular disease: revisiting an old relationship.
      ].
      Table 1The four most cited review articles of “Metabolism” among those published between 2018 and 2022, according to Scopus (www.scopus.com).
      First author [reference]TitleYearCitations
      The articles are sorted according to the total number of citations they have received (last update: October 4, 2022).
      Chooi YC et al.
      • Chooi Y.C.
      • Ding C.
      • Magkos F.
      The epidemiology of obesity.
      The epidemiology of obesity2019854
      Avgerinos KI et al.
      • Avgerinos K.I.
      • Spyrou N.
      • Mantzoros C.S.
      • Dalamaga M.
      Obesity and cancer risk: emerging biological mechanisms and perspectives.
      Obesity and cancer risk: emerging biological mechanisms and perspectives2019345
      Polyzos SA et al.
      • Polyzos S.A.
      • Kountouras J.
      • Mantzoros C.S.
      Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics.
      Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics2019337
      Coliaki C et al.
      • Koliaki C.
      • Liatis S.
      • Kokkinos A.
      Obesity and cardiovascular disease: revisiting an old relationship.
      Obesity and cardiovascular disease: revisiting an old relationship2019202
      a The articles are sorted according to the total number of citations they have received (last update: October 4, 2022).
      Table 2The four most cited original articles of “Metabolism” among those published between 2018 and 2022, according to Scopus (www.scopus.com).
      First author [reference]TitleYearCitations
      The articles are sorted according to the total number of citations they have received (last update: October 4, 2022).
      Palaiodimos L et al.
      • Palaiodimos L.
      • Kokkinidis D.G.
      • Li W.
      • Karamanis D.
      • Ognibene J.
      • Arora S.
      Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York.
      Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York2020448
      Chen X et al.
      • Chen X.
      • Li X.
      • Zhang W.
      • He J.
      • Xu B.
      • Lei B.
      • et al.
      Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-κB pathway.
      Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-κB pathway2018110
      Watanabe M et al.
      • Watanabe M.
      • Caruso D.
      • Tuccinardi D.
      • Risi R.
      • Zerunian M.
      • Polici M.
      • et al.
      Visceral fat shows the strongest association with the need of intensive care in patients with COVID-19.
      Visceral fat shows the strongest association with the need of intensive care in patients with COVID-192020105
      Petersen A et al.
      • Petersen A.
      • Bressem K.
      • Albrecht J.
      • Thieß H.M.
      • Vahldiek J.
      • Hamm B.
      • et al.
      The role of visceral adiposity in the severity of COVID-19: highlights from a unicenter cross-sectional pilot study in Germany.
      The role of visceral adiposity in the severity of COVID-19: highlights from a unicenter cross-sectional pilot study in Germany2020103
      a The articles are sorted according to the total number of citations they have received (last update: October 4, 2022).
      Regarding the top original articles, Palaiodimos et al. were among the first that supported that obesity is associated with higher in-hospital mortality of patients with COVID-19 infection [
      • Palaiodimos L.
      • Kokkinidis D.G.
      • Li W.
      • Karamanis D.
      • Ognibene J.
      • Arora S.
      Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York.
      ], a finding that subsequently was validated by many authors. More specifically, Palaiodimos et al. showed that severe obesity (body mass index [BMI] ≥35 kg/m2 vs. 25–34 kg/m2) conveyed a nearly 4-fold higher risk for in-hospital mortality [
      • Palaiodimos L.
      • Kokkinidis D.G.
      • Li W.
      • Karamanis D.
      • Ognibene J.
      • Arora S.
      Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York.
      ]. In the same year, two other relevant articles on the association between visceral fat and severity of COVID-19 were among the highly cited articles [
      • Watanabe M.
      • Caruso D.
      • Tuccinardi D.
      • Risi R.
      • Zerunian M.
      • Polici M.
      • et al.
      Visceral fat shows the strongest association with the need of intensive care in patients with COVID-19.
      ,
      • Petersen A.
      • Bressem K.
      • Albrecht J.
      • Thieß H.M.
      • Vahldiek J.
      • Hamm B.
      • et al.
      The role of visceral adiposity in the severity of COVID-19: highlights from a unicenter cross-sectional pilot study in Germany.
      ]. Furthermore, Chen et al. showed that AMP-activated Protein Kinase (AMPK) protects against cardiomyocyte injury during ischemia and reperfusion via maintaining mitochondrial function and inhibiting the inflammatory response caused by ischemic insults [
      • Chen X.
      • Li X.
      • Zhang W.
      • He J.
      • Xu B.
      • Lei B.
      • et al.
      Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-κB pathway.
      ].
      Apart from these eight articles, many other articles were recognized in the international scientific community, due to their provocative and stimulating ideas, sound methodology, clear messaging, and research and clinical implications. At the end of the day, publishing in a well-known journal is a scientific accomplishment and provides personal satisfaction, but the upmost scientific recognition is the post-publication acknowledgment of an article through its reading by a global audience and citations in subsequent articles written by other authors.

      3. Article collection from the editors of “Metabolism

      In this section, the Editors of “Metabolism” have each briefly highlighted several important articles in their specific areas of interest. While this is not intended to be a definitive list, the articles mentioned emphasize the quality of studies mainly published over the last three years (2020–2022).

      3.1 COVID-19 infection in metabolic disorders

      The recent COVID-19 pandemic led “Metabolism” to the publication of some high-quality articles on the interconnection between SARS-CoV2 infection and metabolic diseases, early after the outburst of the pandemic. As mentioned above, since the landmark article of Palaiodimos et al. [
      • Palaiodimos L.
      • Kokkinidis D.G.
      • Li W.
      • Karamanis D.
      • Ognibene J.
      • Arora S.
      Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York.
      ], the adverse effect of excessive adiposity, particularly visceral adiposity, on severe disease among patients with COVID-19 has been supported by a number of traditional observational studies and Mendelian randomization studies [
      • Watanabe M.
      • Caruso D.
      • Tuccinardi D.
      • Risi R.
      • Zerunian M.
      • Polici M.
      • et al.
      Visceral fat shows the strongest association with the need of intensive care in patients with COVID-19.
      ,
      • Huang Y.
      • Lu Y.
      • Huang Y.M.
      • Wang M.
      • Ling W.
      • Sui Y.
      • et al.
      Obesity in patients with COVID-19: a systematic review and meta-analysis.
      ,
      • Zhu Z.
      • Hasegawa K.
      • Ma B.
      • Fujiogi M.
      • Camargo Jr., C.A.
      • Liang L.
      Association of obesity and its genetic predisposition with the risk of severe COVID-19: analysis of population-based cohort data.
      ,
      • Favre G.
      • Legueult K.
      • Pradier C.
      • Raffaelli C.
      • Ichai C.
      • Iannelli A.
      • et al.
      Visceral fat is associated to the severity of COVID-19.
      ,
      • Freuer D.
      • Linseisen J.
      • Meisinger C.
      Impact of body composition on COVID-19 susceptibility and severity: a two-sample multivariable mendelian randomization study.
      ,
      • Wang Y.
      • Xu J.
      • Wang Y.
      • Hou H.
      • Feng H.
      • Yang H.
      An updated meta-analysis on the relationship between obesity and COVID-19 mortality.
      ]. Another paper recently published in "Metabolism" showed that poor metabolic health status, either with or without obesity, was associated with a higher risk of critical COVID-19 [
      • Kim N.H.
      • Kim K.J.
      • Choi J.
      • Kim S.G.
      Metabolically unhealthy individuals, either with obesity or not, have a higher risk of critical coronavirus disease 2019 outcomes than metabolically healthy individuals without obesity.
      ]. It is of note that Huang et al. performed a systematic review and meta-analysis of 30 observational studies, including data of over 45,000 participants, to show that obesity increases the odds ratio of hospitalization, admission to intensive care unit, need of invasive mechanical ventilation and mortality among patients with COVID-19 infection [
      • Huang Y.
      • Lu Y.
      • Huang Y.M.
      • Wang M.
      • Ling W.
      • Sui Y.
      • et al.
      Obesity in patients with COVID-19: a systematic review and meta-analysis.
      ]. A subsequent meta-analysis (Du et al.) of 16 observational studies, which included data from approximately 110,000 participants with COVID-19 infection, validated the association of obesity with critical COVID-19 infection and mortality, and additionally, calculated a linear dose-response association between BMI and critical COVID-19 infection and mortality [
      • Du Y.
      • Lv Y.
      • Zha W.
      • Zhou N.
      • Hong X.
      Association of body mass index (BMI) with critical COVID-19 and in-hospital mortality: a dose-response meta-analysis.
      ]: more specifically, for each 1 kg/m2 higher BMI, the odds ratio of critical COVID-19 increases by 9 % and of mortality by 6 % [
      • Du Y.
      • Lv Y.
      • Zha W.
      • Zhou N.
      • Hong X.
      Association of body mass index (BMI) with critical COVID-19 and in-hospital mortality: a dose-response meta-analysis.
      ].
      Other authors focused on the association between COVID-19 infection and vitamin D. Bassatne et al. performed a systematic review and meta-analysis of 31 observational studies and showed that no association was observed between serum 25-hydroxy-vitamin D (25OHD) and mortality, intensive care unit admission, invasive ventilation or non-invasive ventilation [
      • Bassatne A.
      • Basbous M.
      • Chakhtoura M.
      • El Zein O.
      • Rahme M.
      • El-Hajj Fuleihan G.
      The link between COVID-19 and VItamin D (VIVID): a systematic review and meta-analysis.
      ]. The review also identified 32 ongoing clinical trial protocols, implying a topic of high interest. The impact of vitamin D supplementation on modulating immunogenicity post-vaccination is still unclear. The authors underscored that, while biologic plausibility may support an association between vitamin D status and COVID-19 infection, establishing causality remained elusive [
      • Bassatne A.
      • Basbous M.
      • Chakhtoura M.
      • El Zein O.
      • Rahme M.
      • El-Hajj Fuleihan G.
      The link between COVID-19 and VItamin D (VIVID): a systematic review and meta-analysis.
      ]. Indeed, to-date, two years later, several controlled and placebo-controlled vitamin D prevention trials and treatment trials have been published with lingering conflicting results.
      Furthermore, Smolders et al. conducted a proof-of-concept experiment, underscoring that the associations of adverse COVID-19 outcomes and low vitamin D levels could be explained by reverse causality. More specifically, nine healthy, non-smoker, male volunteers received a bolus of 1 ng/kg E. coli-derived lipopolysaccharide (LPS), followed by a continuous infusion of 1 ng/kg/h LPS for 3 h, to induce systemic inflammation. Baseline circulating 25OHD decreased significantly following the start of LPS administration with the lowest concentrations observed 2–3 h after initiation of LPS infusion. The nadir of 25OHD levels coincided with peak levels of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8. 25OHD levels recovered to baseline 6 h following cessation of LPS infusion [
      • Smolders J.
      • van den Ouweland J.
      • Geven C.
      • Pickkers P.
      • Kox M.
      Letter to the editor: vitamin D deficiency in COVID-19: mixing up cause and consequence.
      ]. These data provided alternative explanations for the observed associations between 25OHD and COVID-19 adverse outcomes and highlight the critical need for randomized controlled trials (RCTs) in defining the impact of vitamin D on COVID-19 outcomes and its ensuing complications [
      • Smolders J.
      • van den Ouweland J.
      • Geven C.
      • Pickkers P.
      • Kox M.
      Letter to the editor: vitamin D deficiency in COVID-19: mixing up cause and consequence.
      ].

      3.2 Nonalcoholic fatty liver disease

      Metabolism” has published an increasing volume of articles on NAFLD. Blomdahl et al. performed a study with biopsy-proven NAFLD to show the association between moderate alcohol consumption and liver fibrosis [
      • Blomdahl J.
      • Nasr P.
      • Ekstedt M.
      • Kechagias S.
      Moderate alcohol consumption is associated with advanced fibrosis in non-alcoholic fatty liver disease and shows a synergistic effect with type 2 diabetes mellitus.
      ]. More specifically, although all included patients consumed <140 g alcohol per week, moderate alcohol consumption (defined as >66 g/week) was independently associated with advanced fibrosis (F3-4), as compared to those with lower average alcohol consumption. Notably, the authors also showed an additive effect of moderate alcohol consumption and type 2 diabetes mellitus (T2DM) on advanced fibrosis [
      • Blomdahl J.
      • Nasr P.
      • Ekstedt M.
      • Kechagias S.
      Moderate alcohol consumption is associated with advanced fibrosis in non-alcoholic fatty liver disease and shows a synergistic effect with type 2 diabetes mellitus.
      ]. In another study from the National Health and Nutrition Examination Survey (NHANES 2017–2018) in patients with T2DM, Ciardullo, and Perseghin showed that statin use was independently associated with lower odds of presumable advanced fibrosis (F3-4), as assessed by liver stiffness [
      • Ciardullo S.
      • Perseghin G.
      Statin use is associated with lower prevalence of advanced liver fibrosis in patients with type 2 diabetes.
      ]. This finding is important when considering that NAFLD is a highly prevalent disease without any approved treatment to-date and is in agreement with an expert panel statement previously published in “Metabolism” [
      • Athyros V.G.
      • Alexandrides T.K.
      • Bilianou H.
      • Cholongitas E.
      • Doumas M.
      • Ganotakis E.S.
      The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement.
      ].
      Several papers have also reported adverse cardiometabolic and other health effects associated with NAFLD. Chung et al. demonstrated for the first time in a landmark paper, using data from a cohort of 5,254,786 young adults (aged 20 through 39 years), that NAFLD conveyed a five-fold increased risk of incident T2DM [
      • Chung G.E.
      • Cho E.J.
      • Yoon J.W.
      • Yoo J.J.
      • Chang Y.
      • Cho Y.
      • et al.
      Nonalcoholic fatty liver disease increases the risk of diabetes in young adults: a nationwide population-based study in Korea.
      ]. Liu et al. used a Mendelian randomization design to investigate the potential causal association of NAFLD, by implementing 54 genetic variants associated with chronically elevated alanine transaminase levels, with the risk of 34 extrahepatic diseases [
      • Liu Z.
      • Suo C.
      • Fan H.
      • Zhang T.
      • Jin L.
      • Chen X.
      Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases.
      ]. Their study supported a potentially causal relationship between NAFLD and risk for developing T2DM or diabetic hypoglycemia [
      • Liu Z.
      • Suo C.
      • Fan H.
      • Zhang T.
      • Jin L.
      • Chen X.
      Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases.
      ]. They also provided evidence that NAFLD may be causally associated with increased risk of cholelithiasis, hypertension, coronary artery disease, and heart failure, but with a reduced risk of dementia and pancreatic cancer [
      • Liu Z.
      • Suo C.
      • Fan H.
      • Zhang T.
      • Jin L.
      • Chen X.
      Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases.
      ]. A Mendelian randomization study by Peng et al. also demonstrated that NAFLD was associated with an increased risk of heart failure and additionally with an increased risk of arterial stiffness [
      • Peng H.
      • Wang S.
      • Wang M.
      • Ye Y.
      • Xue E.
      • Chen X.
      • et al.
      Nonalcoholic fatty liver disease and cardiovascular diseases: a mendelian randomization study.
      ]. Another recent study involving 352,911 UK Biobank participants showed that metabolic dysfunction-associated fatty liver disease (MAFLD) was associated with increased risk of 10 of the 24 examined cancers, of which the associations with liver, kidney and thyroid cancers remained significant after adjustment for adiposity [
      • Liu Z.
      • Lin C.
      • Suo C.
      • Zhao R.
      • Jin L.
      • Zhang T.
      • et al.
      Metabolic dysfunction-associated fatty liver disease and the risk of 24 specific cancers.
      ]. Recent data from a large study including 10,585,844 participants and 418,296 deaths during a median follow-up period of 8.3 years showed that the noninvasive index of steatosis, fatty liver index ≥60, may serve as a prognostic indicator of mortality particularly in underweight individuals [
      • Chung G.E.
      • Jeong S.M.
      • Cho E.J.
      • Yoo J.J.
      • Cho Y.
      • Lee K.N.
      • et al.
      Association of fatty liver index with all-cause and disease-specific mortality: a nationwide cohort study.
      ]. Taken together, these findings emphasize the importance of early detection and management of liver pathology in order to reduce the incidence of subsequent diseases.
      Since there are no approved FDA agents to specifically address NAFLD, this topic remains of great interest. Baumann et al. beautifully demonstrated that a peroxisome proliferator-activated receptor (PPAR)-γ antagonist, GW9662 attenuates the progression of NAFLD in mouse experiments [
      • Baumann A.
      • Burger K.
      • Brandt A.
      • Staltner R.
      • Jung F.
      • Rajcic D.
      • et al.
      GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease.
      ]. Kouvari et al. reported that the presence of NAFLD can effectively predict the transition from metabolically healthy obesity into metabolically-unhealthy obesity [
      • Kouvari M.
      • Chrysohoou C.
      • Skoumas J.
      • Pitsavos C.
      • Panagiotakos D.B.
      • Mantzoros C.S.
      • et al.
      The presence of NAFLD influences the transition of metabolically healthy to metabolically unhealthy obesity and the ten-year cardiovascular disease risk: a population-based cohort study.
      ], and Nimer et al. demonstrated that circulating bile acid levels are associated with the transition from simple hepatic steatosis into nonalcoholic steatohepatitis (NASH) [
      • Nimer N.
      • Choucair I.
      • Wang Z.
      • Nemet I.
      • Li L.
      • Gukasyan J.
      • et al.
      Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression.
      ]. In review articles, Longo et al. underscored the critical role of mitochondrial dynamics in the pathophysiology of NAFLD [
      • Longo M.
      • Meroni M.
      • Paolini E.
      • Macchi C.
      • Dongiovanni P.
      Mitochondrial dynamics and nonalcoholic fatty liver disease (NAFLD): new perspectives for a fairy-tale ending?.
      ], Nawrot et al. highlighted the intestine-liver crosstalk in NAFLD, with a specific emphasis on gut microbiota and intestinal permeability/inflammation [
      • Nawrot M.
      • Peschard S.
      • Lestavel S.
      • Staels B.
      Intestine-liver crosstalk in type 2 diabetes and non-alcoholic fatty liver disease.
      ], and Pessoa et al. focused on how novel mechanisms, including dynamic changes in the expression of important hepatic cytoskeletal proteins, are involved in the progression of NAFLD [
      • Pessoa J.
      • Teixeira J.
      Cytoskeleton alterations in non-alcoholic fatty liver disease.
      ].
      As an alternative or adjunct to pharmacological approaches, exercise is an attractive therapeutic strategy for NAFLD. However, knowledge of exercise-mediated intercellular signaling in the liver remains incomplete. A recent study led by Guo et al. identifies Higd1 (mitochondria inner membrane protein)mediated inhibition of the cytosolic oxidized-mtDNA/Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing (NLRP) inflammasome/Janus kinase pathway that facilitates exercise-dependent alleviation of hepatic steatosis [
      • Zhu J.Y.
      • Chen M.
      • Mu W.J.
      • Luo H.Y.
      • Guo L.
      Higd1a facilitates exercise-mediated alleviation of fatty liver in diet-induced obese mice.
      ]. In particular, they found that suppression of hepatic Higd1a in diet-induced obese mice impaired exercise-mediated alleviation of hepatic steatosis, liver injury, and inflammation, while overexpression of hepatic Higd1a ameliorated these effects. These findings may contribute to our understanding of the exercise-mediated beneficial effect of metabolic disorders, such as NAFLD.
      Notably, Sun et al. identified a novel association between liver and kidney disease. Interestingly, MAFLD was shown to identify patients with chronic kidney disease (CKD) better than NAFLD [
      • Sun D.Q.
      • Jin Y.
      • Wang T.Y.
      • Zheng K.I.
      • Rios R.S.
      • Zhang H.Y.
      • et al.
      MAFLD and risk of CKD.
      ]. MAFLD with a higher liver fibrosis score reportedly was strongly and independently associated with CKD and abnormal albuminuria.

      3.3 Insulin resistance, insulin clearance and obesity

      Several papers recently published in “Metabolism” have reported on potential biomarkers of insulin resistance and oxidative stress. For example, Anguita-Ruiz et al. reported for the first time the association of S100A4, a metastasis-associated protein, with insulin resistance and white adipose tissue dysfunction in prepubertal populations [
      • Anguita-Ruiz A.
      • Mendez-Gutierrez A.
      • Ruperez A.I.
      • Leis R.
      • Bueno G.
      • Gil-Campos M.
      • et al.
      The protein S100A4 as a novel marker of insulin resistance in prepubertal and pubertal children with obesity.
      ]. In another landmark paper, Fukuhara et al. demonstrated that human non-mercaptalbumin to mercaptalbumin ratio may be a useful biomarker for oxidative stress in elderly patients with diabetes [
      • Fukuhara S.
      • Yasukawa K.
      • Sato M.
      • Ikeda H.
      • Inoguchi Y.
      • Etoh T.
      • et al.
      Clinical usefulness of human serum nonmercaptalbumin to mercaptalbumin ratio as a biomarker for diabetic complications and disability in activities of daily living in elderly patients with diabetes.
      ].
      Obesity has also been demonstrated to impact long-term survival after liver transplantation. In a landmark study by van Son et al. obesity, at 1-year post-transplantation, conferred a 2-fold higher risk of mortality [
      • van Son J.
      • Stam S.P.
      • Gomes-Neto A.W.
      • Oste M.C.J.
      • Blokzijl H.
      • van den Berg A.P.
      • et al.
      Post-transplant obesity impacts long-term survival after liver transplantation.
      ]. This study further showed that BMI was inversely associated with 15-year survival, independently of age, sex, transplant characteristics, muscle mass, cardiovascular risk factors, kidney- and liver function [
      • van Son J.
      • Stam S.P.
      • Gomes-Neto A.W.
      • Oste M.C.J.
      • Blokzijl H.
      • van den Berg A.P.
      • et al.
      Post-transplant obesity impacts long-term survival after liver transplantation.
      ]. These findings underscore the importance of intervention strategies aimed at reducing adiposity to improve long-term survival after liver transplantation.
      Following the revolutionary introduction of fibronectin type III domain-containing protein (FNDC)5 and irisin some 10 years ago [
      • Polyzos S.A.
      • Kountouras J.
      • Shields K.
      • Mantzoros C.S.
      Irisin: a renaissance in metabolism?.
      ], Frühbeck et al. studied FNDC4, a peptide showing high homology with FNDC5, but exhibiting a different expression profile, in response to exercise and inflammation [
      • Frühbeck G.
      • Fernández-Quintana B.
      • Paniagua M.
      • Hernández-Pardos A.W.
      • Valentí V.
      • Moncada R.
      • et al.
      FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes.
      ]. Lower concentrations of circulating FNDC4 were observed in patients with morbid obesity than normal-weighted individuals and they remained unaffected by bariatric surgery in the former group [
      • Frühbeck G.
      • Fernández-Quintana B.
      • Paniagua M.
      • Hernández-Pardos A.W.
      • Valentí V.
      • Moncada R.
      • et al.
      FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes.
      ]. The authors also showed that stimuli emanating from adipose tissue regulated FNDC4 and, vice versa, FNDC4 reduced lipid accumulation while stimulating the “brownish” of visceral adipocytes [
      • Frühbeck G.
      • Fernández-Quintana B.
      • Paniagua M.
      • Hernández-Pardos A.W.
      • Valentí V.
      • Moncada R.
      • et al.
      FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes.
      ], a process similar to that induced by irisin. These findings may have certain research and clinical implications, since the management of obesity is today extremely important as outlined earlier.
      In addition to actions to improve the public awareness of the adverse health effects linked to obesity, there is a need for effective strategies to reduce the prevalence of obesity, worldwide. A systematic review and meta-analysis of RCTs published in “Metabolism” showed that alternate-day fasting can be an effective approach to lower adiposity and total cholesterol concentrations in overweight adults [
      • Park J.
      • Seo Y.G.
      • Paek Y.J.
      • Song H.J.
      • Park K.H.
      • Noh H.M.
      Effect of alternate-day fasting on obesity and cardiometabolic risk: a systematic review and meta-analysis.
      ]. However, more studies are warranted to show the safety and efficacy of alternate fasting programs in individuals with obesity and related diseases.
      An important consideration in the overall effect of insulin and states of impaired metabolism is insulin clearance. The hypothesis that insulin-degrading enzyme (IDE) controls postprandial insulin clearance and hepatic IDE dysfunction promote dysmetabolic responses and prediabetes traits such, as hepatic steatosis, was tested by Borges et al. [
      • Borges D.O.
      • Patarrão R.S.
      • Ribeiro R.T.
      • de Oliveira R.M.
      • Duarte N.
      • Belew G.D.
      • et al.
      Loss of postprandial insulin clearance control by insulin-degrading enzyme drives dysmetabolism traits.
      ]. They found that postprandial insulin clearance is strongly associated with the IDE gene variation in a European/Portuguese population-based cohort. Interestingly, this effect is found in men population and is abolished in prediabetic conditions. Liver-specific deletion of IDE leads to a significant decrease in postprandial insulin clearance during the oral glucose tolerance test in mice fed a normal chow diet. Under high-fat feeding, liver-specific IDE-deficient mice have increased hepatic fat accumulation [
      • Borges D.O.
      • Patarrão R.S.
      • Ribeiro R.T.
      • de Oliveira R.M.
      • Duarte N.
      • Belew G.D.
      • et al.
      Loss of postprandial insulin clearance control by insulin-degrading enzyme drives dysmetabolism traits.
      ]. Overall, this study appears to be crucial to the field as it provides a new mechanism underlying IDE-mediated postprandial insulin clearance and the importance of human IDE genetic effects on postprandial insulin clearance.

      3.4 Renal disease in diabetes mellitus

      Metabolism” has also published interesting and important articles on renal disease in diabetes. Wu et al. have described that inhibition of NLRP3 inflammasome protects against podocyte damage in diabetic nephropathy through suppression of lipid accumulation [
      • Wu M.
      • Yang Z.
      • Zhang C.
      • Shi Y.
      • Han W.
      • Song S.
      • et al.
      Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy.
      ]. Thus, the inhibition of NLRP3 inflammasome activation is proposed as a novel therapeutic approach for diabetic kidney disease. Loretelli et al. describe how the axis IL-8/CXC chemokine receptors (CXCR)1/2 may have a role in diabetic kidney disease by inducing podocyte damage [
      • Loretelli C.
      • Rocchio F.
      • D'Addio F.
      • Ben Nasr M.
      • Castillo-Leon E.
      • Dellepiane S.
      • et al.
      The IL-8-CXCR1/2 axis contributes to diabetic kidney disease.
      ]. Targeting the IL-8-CXCR1/2 axis may thus reduce the burden of diabetic kidney disease. Zhang et al. has observed how brown adipose tissue (BAT)-derived miRNAs might be a promising target for kidney protection in diabetes mellitus. BAT transplantation, via increased circulating miR-30b levels, was shown to ameliorate diabetic kidney disease [
      • Zhang Y.
      • Cai Y.
      • Zhang H.
      • Zhang J.
      • Zeng Y.
      • Fan C.
      • et al.
      Brown adipose tissue transplantation ameliorates diabetic nephropathy through the miR-30b pathway by targeting Runx1.
      ]. This fascinating advancement linking BAT and vascular complications in diabetes points towards novel mechanisms and potentially identifies putative novel targets for treatment of diabetic kidney disease. Yang et al. proposed that mammalian serine/threonine-protein kinase 4 (MST1) activation represents a potential therapeutic strategy to prevent/reduce the fibrosis seen in diabetic kidney disease [
      • Yang T.
      • Heng C.
      • Zhou Y.
      • Hu Y.
      • Chen S.
      • Wang H.
      • et al.
      Targeting mammalian serine/threonine-protein kinase 4 through yes-associated protein/TEA domain transcription factor-mediated epithelial-mesenchymal transition ameliorates diabetic nephropathy orchestrated renal fibrosis.
      ,
      • Yang T.
      • Heng C.
      • Zhou Y.
      • Hu Y.
      • Chen S.
      • Wang H.
      • et al.
      Corrigendum to 'Targeting mammalian serine/threonine-protein kinase 4 through yes-associated protein/TEA domain transcription factor-mediated epithelial-mesenchymal transition ameliorates diabetic nephropathy orchestrated renal fibrosis [Metabolism clinical and experimental 108 (2020) 154258].
      ]. Additional studies should likely be conducted to explore the role of this pathway in non-diabetic, fibrotic, renal diseases. Luo et al. provided an interesting observation relating increased ornithine catabolism to the compromised glycolysis in podocytes observed under diabetic conditions [
      • Luo Q.
      • Liang W.
      • Zhang Z.
      • Zhu Z.
      • Chen Z.
      • Hu J.
      • et al.
      Compromised glycolysis contributes to foot process fusion of podocytes in diabetic kidney disease: role of ornithine catabolism.
      ]. The metabolites of ornithine catabolism appear to contribute to cytoskeletal remodeling that could favor podocyte detachment in diabetic kidney disease.

      3.5 Cardiovascular dysfunction in cardiometabolic and cardio-renal syndromes

      An additional area that is receiving increased attention in “Metabolism” relates to the risk for developing cardiovascular disease in states of disordered metabolism, including the so-called cardiometabolic and cardio-renal syndromes. Beyond diabetes per se obesity, insulin resistance and NAFLD are appreciated to contribute to the development of cardiovascular diseases, which remain a major cause of morbidity and mortality in western and developing societies.
      Endothelial cell dysfunction has been shown to be an early marker of metabolically related vascular disease in both human studies and experimental animal models. In an elegant basic science study of isolated small arteries, Wilson et al. used sophisticated intracellular fluorescence Ca2+-imaging approaches to demonstrate a functional network of endothelial cells characterized by sub-populations of clustered specialized agonist-sensing cells, from which signals were communicated through the network to elicit vasodilation [
      • Wilson C.
      • Zhang X.
      • Lee M.D.
      • MacDonald M.
      • Heathcote H.R.
      • Alorfi N.M.N.
      • et al.
      Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity.
      ]. In contrast, in a pre-diabetic rat model of obesity (high fat feeding) the number of these specialized cell clusters was decreased (increasing the distance between functional sensing units) and endothelial dependent dilation impaired. Importantly, endothelial Ca2+ levels contribute to the regulation of endothelial derived hyperpolarizing processes important in vasodilation and regulate the synthesis and release of vasoactive mediators, such as nitric oxide. In a related study, Mishra et al. showed that altered endothelial cell Ca2+ handling and resistance artery dysfunction in Goto-Kakizaki rats, a model of T2DM, could be attenuated by a "priming" dose of a small molecular weight activator (Small conductance K-channel Activators [SKA]-31) of Ca2+-activated K+ channels (KCa2.3 and KCa3.1) [
      • Mishra R.C.
      • Kyle B.D.
      • Kendrick D.J.
      • Svystonyuk D.
      • Kieser T.M.
      • Fedak P.W.M.
      • et al.
      KCa channel activation normalizes endothelial function in type 2 diabetic resistance arteries by improving intracellular Ca(2+) mobilization.
      ]. While the dose of the SKA-31 did not itself elicit direct vasoactive effects, its priming effect on Ca2+-activated ion channels improved endothelial-dependent vasomotor function in the diabetic situation. Collectively, such studies identify mechanisms underlying metabolically-induced arterial dysfunction and provide putative molecular targets for potential vascular-directed therapeutic intervention.
      Abnormally increased vascular stiffness is a further predictor of vascular dysfunction and is related to the likelihood of future adverse cardiovascular events. Vascular stiffening is a complex and likely multi-factorial process involving alterations in the properties of extracellular (including matrix proteins and calcification) and cellular (endothelial, smooth muscle and adventitial cells) components of the vessel wall. Several recent papers published in "Metabolism" have addressed cellular mechanisms by which metabolic dysfunction may underly abnormal vascular stiffening mediated by altered vascular structure and function [
      • Sowers J.R.
      • Habibi J.
      • Jia G.
      • Bostick B.
      • Manrique-Acevedo C.
      • Lastra G.
      • et al.
      Endothelial sodium channel activation promotes cardiac stiffness and diastolic dysfunction in Western diet fed female mice.
      ,
      • Ong K.L.
      • McClelland R.L.
      • Allison M.A.
      • Cushman M.
      • Garg P.K.
      • Tsai M.Y.
      • et al.
      Lipoprotein (a) and coronary artery calcification: prospective study assessing interactions with other risk factors.
      ].
      Of direct clinical relevance, Phan et al. conducted a longitudinal study to examine changes in arterial stiffness (as assessed by pulse wave velocity [PWV]) and pulse wave reflection in subjects at high risk for developing the pregnancy-related hypertensive syndrome, pre-eclampsia [
      • Phan K.
      • Schiller I.
      • Dendukuri N.
      • Gomez Y.H.
      • Gorgui J.
      • El-Messidi A.
      • et al.
      A longitudinal analysis of arterial stiffness and wave reflection in preeclampsia: identification of changepoints.
      ]. Baseline measurements using applanation tonometry were taken at 10–13 weeks gestation and at 4-week intervals, thereafter. Carotid-femoral PWV and augmentation index increased in women who subsequently developed pre-eclampsia (compared to those who did not) at 22–25 and 18–21 weeks of gestation, respectively. The authors concluded that these findings show the potential clinical utility of arterial stiffness and wave reflection measurements as an early screening tool for pre-eclampsia, which can be used as an important and needed tool for informing clinical management of high-risk pregnancies.
      In addition to vascular dysfunction, metabolic disease is associated with cardiac abnormalities including heart failure. Altered cardiac metabolism and its contribution to cardiac hypertrophy and dysfunction have been studied in “Metabolism” papers describing both pre-clinical models [
      • Uddin G.M.
      • Karwi Q.G.
      • Pherwani S.
      • Gopal K.
      • Wagg C.S.
      • Biswas D.
      • et al.
      Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart.
      ] and human subjects [
      • Monzo L.
      • Sedlacek K.
      • Hromanikova K.
      • Tomanova L.
      • Borlaug B.A.
      • Jabor A.
      • et al.
      Myocardial ketone body utilization in patients with heart failure: the impact of oral ketone ester.
      ]. Uddin et al. using cardiac-specific mouse knockout models examined the relative contributions of branched chain amino acids (BCAA) and branched chain ketoacids (BCKA) to events related to insulin-stimulated glucose oxidation [
      • Uddin G.M.
      • Karwi Q.G.
      • Pherwani S.
      • Gopal K.
      • Wagg C.S.
      • Biswas D.
      • et al.
      Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart.
      ]. The authors concluded a specific role for BCKAs and that decreasing their levels may provide an option for improving cardiac insulin sensitivity. In a clinical study, Monzo et al. examined ketone utilization in heart failure patients with reduced ejection fraction and its relationship to cardiac dysfunction and remodeling [
      • Monzo L.
      • Sedlacek K.
      • Hromanikova K.
      • Tomanova L.
      • Borlaug B.A.
      • Jabor A.
      • et al.
      Myocardial ketone body utilization in patients with heart failure: the impact of oral ketone ester.
      ]. These authors suggested that early heart failure may benefit from administration of exogenous ketones due to an enhanced capacity of the heart to utilize β-OH butyrate. In an additional clinical study, Luong et al. in a study using 18F-fluorodeoxyglucose positron emission tomography scanning and a hyperinsulinemic-euglycemic clamp approach asked the question whether cardiac (specific) insulin resistance would predict outcomes (mortality and major cardiovascular events) in heart failure patients undergoing revascularization [
      • Luong T.V.
      • Pedersen M.G.B.
      • Kjærulff M.
      • Madsen S.
      • Lauritsen K.M.
      • Tolbod L.P.
      • et al.
      Ischemic heart failure mortality is not predicted by cardiac insulin resistance but by diabetes per se and coronary flow reserve: a retrospective dynamic cardiac (18)F-FDG PET study.
      ]. These authors found that, while ischemic heart failure mortality was not predicted by cardiac insulin resistance, the presence of diabetes and impaired coronary flow reserve (an indicator of impaired microvascular function) were predictive of overall survival.
      The positive cardiovascular/cardio-renal effects of novel anti-diabetic agents (including the sodium-glucose cotransporter [SGLT]-2 inhibitors and glucagon-like peptide-1 receptor agonists [GLP-1RA]) has stimulated intense interest in their mechanisms of action. This has been heightened by positive outcomes having been demonstrated in heart failure (both with reduced or preserved ejection fraction) trials in subjects with and without diabetes. In January of 2022, Liu et al. published an excellent review on cardiorenal protection by SGLT-2 inhibitors in subjects with T2DM [
      • Liu H.
      • Sridhar V.S.
      • Boulet J.
      • Dharia A.
      • Khan A.
      • Lawler P.R.
      • et al.
      Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease.
      ]. In this extensive review the authors first describe mechanisms by which SGLT-2 inhibitors may exert beneficial effects, including modulation of the renin-angiotensin-aldosterone system and its impact on kidney function (including regulation of tubuloglomerular feedback), energy substrate utilization and attenuation of systemic inflammation and oxidative stress [
      • Liu H.
      • Sridhar V.S.
      • Boulet J.
      • Dharia A.
      • Khan A.
      • Lawler P.R.
      • et al.
      Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease.
      ]. These mechanisms are then discussed in the context of cardiorenal protection. A further review from Sachinidis et al. specifically examined cardiovascular outcome trials for incretin-based medications emphasizing the positive cardiovascular benefits of the GLP-1RAs [
      • Sachinidis A.
      • Nikolic D.
      • Stoian A.P.
      • Papanas N.
      • Tarar O.
      • Rizvi A.A.
      • et al.
      Cardiovascular outcomes trials with incretin-based medications: a critical review of data available on GLP-1 receptor agonists and DPP-4 inhibitors.
      ]. Beyond the novel anti-diabetic agents, interest continues on the pleiotropic effects of older agents including metformin [
      • Triggle C.R.
      • Mohammed I.
      • Bshesh K.
      • Marei I.
      • Ye K.
      • Ding H.
      • et al.
      Metformin: is it a drug for all reasons and diseases?.
      ,
      • Schernthaner G.
      • Brand K.
      • Bailey C.J.
      Metformin and the heart: update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure.
      ]. In this regard, Scherbthaner et al. reviewed the cardioprotective effects of metformin, particularly as relates to heart failure, while pointing out that due to the “age” of this drug it has not benefitted from the extensive cardiovascular outcome trials that have been afforded to the SGLT-2 inhibitors and GLP-1RAs [
      • Schernthaner G.
      • Brand K.
      • Bailey C.J.
      Metformin and the heart: update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure.
      ]. Similarly, the role of insulin as a vasoactive factor was reviewed by Natali and Nesti emphasizing the presence of functional insulin receptors on endothelial and smooth muscle cells [
      • Natali A.
      • Nesti L.
      Vascular effects of insulin.
      ].
      Related to the use and novel actions of SGLT-2 inhibitors, two intriguing, clinically relevant, papers have been recently published in “Metabolism”. Marfella et al. reported that, in diabetic subjects having undergone heart transplantation, those subjects that continued to be treated with SGLT-2 inhibitors exhibited less evidence for the early development of cardiomyopathy as suggested by JunD/PPAR-γ overexpression, lipid accumulation and impaired insulin receptor substrate-1/ and -2 signaling [
      • Marfella R.
      • D'Onofrio N.
      • Trotta M.C
      • Sardu C.
      • Scisciola L.
      • Amarelli C.
      • et al.
      Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts.
      ]. Although direct causality was not addressed, these alterations in signaling were attenuated in patients treated with SGLT-2 inhibitors. In the second study Sardu et al. showed that vasovagal syndrome recurrence was decreased in diabetic subjects treated with SGLT-2 inhibitors [
      • Sardu C.
      • Massimo Massetti M.
      • Rambaldi P.
      • Gatta G.
      • Cappabianca S.
      • Sasso F.C.
      • et al.
      SGLT2-inhibitors reduce the cardiac autonomic neuropathy dysfunction and vaso-vagal syncope recurrence in patients with type 2 diabetes mellitus: the SCAN study.
      ]. The authors proposed that SGLT-2 inhibitors improve autonomic dysfunction although other mechanisms cannot be discounted. While these early-stage clinical observations do not provide exact mechanisms of action for the SGLT-2 inhibitors, they emphasize the possible diversity of effects of these agents and provide the impetus for additional mechanistic investigation.
      Future studies will continue to delineate mechanisms by which dysregulated metabolism leads to cardiovascular dysfunction and ultimately to understanding its causal role in clinically relevant vascular diseases, including heart failure, renal impairment, cerebrovascular disease (including stroke and cognitive impairment) and microvascular dysfunction.

      3.6 Metabolic bone diseases and muscle-bone-fat crosstalk

      The skeleton is indeed an epicenter for metabolic signaling pathways. This fascinating narrative has been unfolding over some 7 decades, and is further illustrated through selected recent publications from our journal. The Mechanostat, and the Muscle-Bone Unit, are terms coined by the famous orthopedic surgeon Harold Frost in the 1960s to describe the critical role mechanical loading plays in modulating bone structure and mass across the life span [
      • Frost H.M.
      • Schönau E.
      The, "Muscle-bone Unit" in children and adolescents: a 2000 overview.
      ]. The seminal papers of Frost underscore the tight anatomical and physiological connection between these two crucial organs (i.e., bone and skeletal muscle) to locomotion and survival. A couple of decades later the concept of bone-fat cross-talk sparked interest with the discovery of intriguing modulatory pathways of bone marrow multipotent stem cells, differentiating into either adipocytes or osteoblasts [
      • Beresford J.N.
      • Bennett J.H.
      • Devlin C.
      • Leboy P.S.
      • Owen M.E.
      Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures.
      ]. More recently, the advent of newer and powerful molecular tools enabled the concomitant interrogation of a wide range of closely interconnected signaling pathways, through the exquisitely orchestrated interplay among myokines, adipokines and osteokines. These factors exert autocrine, paracrine and endocrine effects, thus regulating energy expenditure and metabolism [
      • Kirk B.
      • Feehan J.
      • Lombardi G.
      • Duque G.
      Muscle, bone, and fat crosstalk: the biological role of myokines, osteokines, and adipokines.
      ].
      Irisin might be a major regulator of the cross-talk between muscle and bone. This myokine is mainly produced by the skeletal muscle in mice in response to exercise and possibly in humans. Anastasilakis et al. summarized evidence for a putative beneficial effect of irisin on several metabolic disorders, especially those known to exhibit beneficial effects of exercise (such as T2DM). Exercise is a potent stimulus for bone formation, improving bone mineral density, mainly through loading on the skeleton, thus reducing fracture risk. Modulation of the irisin pathway may improve insulin resistance and bone density [
      • Anastasilakis A.D.
      • Polyzos S.A.
      • Makras P.
      • Douni E.
      • Mantzoros C.S.
      Irisin: good or bad for the bone? A new path forward after the reported discovery of irisin receptor?.
      ], however, more studies are required in this field.
      Diabetes is associated with an increased risk of bone fragility and fracture. Several possible mechanisms have been suggested, including poor glycemic control, obesity, advanced glycation end products and inflammation. Interestingly, high variability in glucose control and weight fluctuation may be additional predisposing factors. In a population-based cohort study of 480,539 subjects over 40 years, followed for 8.1 years, Lee et al. observed that 2834 (0.59 %) of them experienced hip fractures. The hazard ratios (HRs) (95 % CI) of hip fracture were 1.36 (1.24–1.50) and 1.29 (1.16–1.43) for high body weight variability independent of the mean (VIM) and high glucose VIM, respectively, after adjustment for potential confounders [
      • Lee J.
      • Han K.
      • Park S.H.
      • Kim M.K.
      • Lim D.J.
      • Yoon K.H.
      • et al.
      Associations of variability in body weight and glucose levels with the risk of hip fracture in people with diabetes.
      ].
      The role of Sprouty (SPRY) proteins, which play critical roles in controlling cell proliferation, differentiation, and survival, in the regulation of osteogenic and/or adipogenic differentiation of mesenchymal stem cells (MSCs) was recently investigated. Tian et al. suggested that the presence of a novel SPRY4-extracellular signal-regulated kinase (ERK)1/2-wingless (Wnt)/β-catenin regulatory pathway in marrow stromal progenitor cells plays a key role in cell fate determination in mice [
      • Tian L.
      • Xiao H.
      • Li M.
      • Wu X.
      • Xie Y.
      • Zhou J.
      • et al.
      A novel Sprouty4-ERK1/2-Wnt/β-catenin regulatory loop in marrow stromal progenitor cells controls osteogenic and adipogenic differentiation.
      ]. This pathway may provide a novel therapeutic target for the treatment of metabolic bone disorders, such as osteoporosis.
      Steroids may alter the balance between differentiation of MSCs into either adipocytes or osteoblasts. In a series of elegant experiments conducted in wild type (WT) and Dexras1 knockout (KO) mouse models exposed to glucocorticoids, Seok et al. showed that Dexras1 deficiency was associated with increased osteogenesis, concurrent with reduced adipogenesis, evaluated by dual-energy X-ray absorptiometry and micro-computed tomography analyses, in murine femora [
      • Seok J.W.
      • Kim D.
      • Yoon B.K.
      • Lee Y.
      • Kim H.J.
      • Hwang N.
      • et al.
      Dexras1 plays a pivotal role in maintaining the equilibrium between adipogenesis and osteogenesis.
      ]. Dexras1 deficiency promoted osteogenesis of bone marrow MSCs, suggesting that Dexras1 deficiency also prevents steroid-induced osteoporosis. Thus, Dexras1 may play a key role in maintaining the equilibrium between adipogenesis and osteogenesis in response to steroid treatment [
      • Seok J.W.
      • Kim D.
      • Yoon B.K.
      • Lee Y.
      • Kim H.J.
      • Hwang N.
      • et al.
      Dexras1 plays a pivotal role in maintaining the equilibrium between adipogenesis and osteogenesis.
      ]. Steroid therapy is still widely used in pulmonary and rheumatologic conditions. It increases visceral adiposity, leading to insulin resistance, and results in fragility fractures in over 50 % of patients on chronic treatment. Drug development targeting this pathway may provide needed options to prevent and treat such ensuing debilitating morbidities.
      Bone morphogenetic proteins (BMPs) were originally discovered through their ability to induce formation of bone and cartilage. They are recognized as a family of ligands which play important roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment, morphogenesis, differentiation, proliferation and apoptosis of various cell types, thus orchestrating tissue architecture. BMP ligands, receptors, and inhibitors are also found throughout plastic adult brain regions. Jensen et al. reviewed the role of BMPs in controlling metabolic health through central actions in the brain, as well as in peripheral tissues, such as the adipose tissue [
      • Jensen G.S.
      • Leon-Palmer N.E.
      • Townsend K.L.
      Bone morphogenetic proteins (BMPs) in the central regulation of energy balance and adult neural plasticity.
      ].
      There has been an explosion of publications related to vitamin D over the last 5 decades. A simple Pubmed search reveals over 97,000 publications during that period, a number that is largely explained by the potentially pleotropic effects of vitamin D on the immune system, cardiovascular system and cancer. Christakos et al. reviewed latest evidence of principal effects of vitamin D on endocrine system and addressed clinical syndromes related to abnormalities in vitamin D metabolism and action [
      • Christakos S.
      • Li S.
      • De La Cruz J.
      • Bikle D.D.
      New developments in our understanding of vitamin metabolism, action and treatment.
      ].
      Vitamin D deficiency is common in obese individuals and during weight loss. Current vitamin D guidelines in obesity are based on low quality evidence and were for the most part not based on rigorously conducted systematic reviews and meta-analyses. Bassatne et al. performed a systematic review consisting of 13 RCTs of vitamin D supplementation in obese individuals during weight loss (six medication-treated and seven after bariatric surgery) [
      • Bassatne A.
      • Chakhtoura M.
      • Saad R.
      • Fuleihan G.E.
      Vitamin D supplementation in obesity and during weight loss: a review of randomized controlled trials.
      ]. The authors reported that vitamin D doses ≥1600–2000 IU/d may be needed to reach a 25OHD concentration ≥30 ng/ml in obese individuals and following bariatric surgery. The optimal concentration in this population is unknown, and whether the above suggested doses protect against weight loss-induced bone loss and fragility fractures is not yet certain. There was no clear evidence for a beneficial effect of vitamin D supplementation on cardio-metabolic parameters in obese individuals, and data on such parameters during weight loss remain scarce. Thus, well-designed long-term clinical trials assessing the effect of vitamin D supplementation during weight loss in obese subjects are needed.

      3.7 Immunometabolism

      Studies of the immune system and those of metabolism have been historically considered two separate disciplines. However, over the past few years, the role played by the immune system in the pathogenesis of different metabolic disorders, such as diabetes, obesity and NAFLD, has become increasingly recognized, giving rise to a branch of immunology called “immunometabolism”. In this area of research, rising interest has been directed towards the study of macrophages, which reside in or infiltrate metabolic organs causing the so-called “low-grade inflammation”, which in turns leads to the development of metabolic syndrome and its associated complications. Compelling experimental evidence has indeed suggested that resident macrophages perceive molecular signals, which are able to modulate their phenotypic/functional features, favoring a polarization towards an activated phenotype, classically defined as M1. In this context, a series of chemokines coordinate leukocyte activation and migration to the inflamed site.
      Xu et al. investigated the role of C-C chemokine ligand (CCL)3 in the development of NAFLD [
      • Xu L.
      • Chen Y.
      • Nagashimada M.
      • Ni Y.
      • Zhuge F.
      • Chen G.
      • et al.
      CC chemokine ligand 3 deficiency ameliorates diet-induced steatohepatitis by regulating liver macrophage recruitment and M1/M2 status in mice.
      ]. They found that increased levels of CCL3 sustained liver infiltration by macrophages, which displayed a pro-inflammatory M1-like phenotype. On the contrary, CCL3-deficient mice showed a significant reduction in hepatic recruitment of T-cells and macrophages that switched towards a M2 phenotype, as compared to WT counterparts. Moreover, mutant mice were protected from hepatic inflammation, NASH, hepatic fibrosis and diet-induced insulin resistance [
      • Xu L.
      • Chen Y.
      • Nagashimada M.
      • Ni Y.
      • Zhuge F.
      • Chen G.
      • et al.
      CC chemokine ligand 3 deficiency ameliorates diet-induced steatohepatitis by regulating liver macrophage recruitment and M1/M2 status in mice.
      ], thus highlighting the pivotal role of CCL3 in the control of macrophage activation in NAFLD.
      Macrophage polarization has also been shown to be crucial for the progression of T2DM, in which a high lipidic environment enhances macrophage activation. However, the specific molecular mechanisms underlying this phenomenon were not entirely clear, until the study performed by Wang et al., which added an important piece to this complex scenario [
      • Wang X.
      • Chen S.
      • He J.
      • Chen W.
      • Ding Y.
      • Huang J.
      • et al.
      Histone methyltransferases G9a mediated lipid-induced M1 macrophage polarization through negatively regulating CD36.
      ]. The authors showed that lipids (i.e., palmitate) promoted macrophage M1 polarization, decreasing the expression of the enzyme histone methyltransferase G9a and this enzyme, in turn, negatively regulated the expression of the fatty acid transport protein CD36. The model proposed by the authors assumed that CD36 expression (induced by high lipid levels) was controlled by G9a inhibition and this condition promoted lipid accumulation in the macrophages, favoring endoplasmic reticulum (ER) stress and pro-inflammatory macrophage polarization, thereby contributing to T2DM development.
      Furthermore, macrophages, having been recently characterized for their role in the control of tumor growth, and obesity, diabetes and associated NASH, are considered risk factors for the development of hepatocellular carcinoma (HCC). In this context, the study by Van Campenhout et al. shed light on the role of inositol-requiring enzyme 1 alpha (IRE1α), an ER stress protein, on the progression of NASH to HCC [
      • Van Campenhout S.
      • Tilleman L.
      • Lefere S.
      • Vandierendonck A.
      • Raevens S.
      • Verhelst X.
      • et al.
      Myeloid-specific IRE1alpha deletion reduces tumour development in a diabetic, non-alcoholic steatohepatitis-induced hepatocellular carcinoma mouse model.
      ]. The authors found that myeloid-specific IRE1α knock-out mice (myeloid IRE1α-KO) show reduced weight gain and improved glucose tolerance upon high-fat diet and their adipose tissue macrophages displayed a prominent anti-inflammatory phenotype, thus slowing down HCC development. These events were also analyzed at the transcriptional level, comparing the global expression profile of different cell subsets (Kupffer cells, macrophages and monocytes) from WT vs. IRE1α-KO mice. The results revealed profound differences in those genes/pathways involved in cell adhesion, fibrogenesis, lipid metabolism and immune system activation, between the two groups of mice [
      • Van Campenhout S.
      • Tilleman L.
      • Lefere S.
      • Vandierendonck A.
      • Raevens S.
      • Verhelst X.
      • et al.
      Myeloid-specific IRE1alpha deletion reduces tumour development in a diabetic, non-alcoholic steatohepatitis-induced hepatocellular carcinoma mouse model.
      ].
      Taken together, all these studies have a high translational potential and clinical relevance. In fact, the identification of pivotal molecules involved in the process of macrophage activation (i.e., CCL3, G9a, IRE1α), may lead to novel therapeutic strategies for immune-mediated and dysmetabolic conditions, characterized by macrophage dysregulation. Since all these studies have been performed in mice models of diseases, they need to be confirmed in the human setting. Next, the main challenge of scientific research will be to design novel drugs targeting the above-mentioned molecules, in an effort to better elucidate the potential of new specific inhibitors as a bridge to human pathology and treatment perspective.
      In addition to macrophages, also other innate immune cells, such as natural killer (NK) cells, have been studied in the context of metabolic disorders. Hu et al. found impaired number and function of NK cells in Apoc3TG mice, a transgenic model characterized by high levels of plasma triglyceride and free fatty acids [
      • Hu X.
      • Jia X.
      • Xu C.
      • Wei Y.
      • Wang Z.
      • Liu G.
      • et al.
      Downregulation of NK cell activities in apolipoprotein C-III-induced hyperlipidemia resulting from lipid-induced metabolic reprogramming and crosstalk with lipid-laden dendritic cells.
      ]. From a metabolic perspective, the reduced function of NK cells induced by hyperlipidemia was due to increased fatty acid oxidation and decreased glycolysis in NK cells. Furthermore, the authors also demonstrated that Apoc3TG-dendritic cells (DCs), containing more lipids in their cytoplasm, contributed to the suppression of NK cell activity, via reactive oxygen species-induced expression of programmed death-ligand (PD-L1), NK group 2, member D ligand (NKG2DL) and transforming growth factor (TGF)-β1 [
      • Hu X.
      • Jia X.
      • Xu C.
      • Wei Y.
      • Wang Z.
      • Liu G.
      • et al.
      Downregulation of NK cell activities in apolipoprotein C-III-induced hyperlipidemia resulting from lipid-induced metabolic reprogramming and crosstalk with lipid-laden dendritic cells.
      ]. Taken together, these data may be crucial for the management of metabolic disorders; indeed, they suggest the importance of appropriate plasma lipid level to control NK cell activity, to avoid their impairment and metabolic reprograming induced by excess of lipids, generally observed in obesity and metabolic syndrome.

      3.8 Central nervous system and neuroendocrine interactions

      In the area of central nervous system, Jensen et al., as mentioned above, underscored the unique role of BMPs in the central regulation of energy balance and neural plasticity [
      • Jensen G.S.
      • Leon-Palmer N.E.
      • Townsend K.L.
      Bone morphogenetic proteins (BMPs) in the central regulation of energy balance and adult neural plasticity.
      ], and Metz et al. highlighted the potential involvement of oral contraceptives in difficulty in weight loss of obese women [
      • Metz L.
      • Isacco L.
      • Redman L.M.
      Effect of oral contraceptives on energy balance in women: a review of current knowledge and potential cellular mechanisms.
      ]. van Galen et al. demonstrated that lean men respond well to prolonged fasting by increasing hypothalamic serotonin transporter availability, whereas such a response is absent in obese men [
      • van Galen K.A.
      • Booij J.
      • Schrantee A.
      • Adriaanse S.M.
      • Unmehopa U.A.
      • Fliers E.
      • et al.
      The response to prolonged fasting in hypothalamic serotonin transporter availability is blunted in obesity.
      ]. Gavini et al. reported that hypothalamic C2-domain protein is regulated by metabolic cues in mice and is involved in melanocortin 4 receptor (MC4R) trafficking and appetite control [
      • Gavini C.K.
      • Cook T.M.
      • Rademacher D.J.
      • Mansuy-Aubert V.
      Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance.
      ], thus representing a novel candidate for therapy of obesity.
      Responding appropriately to physiological energy stress, such as satiety/hunger, and maintaining the balance of endocrine hormones are essential for ensuring energy homeostasis in our body. Related to this, Yang et al. focused on neuronal primary cilia as a cellular organelle for a proper homeostatic response to these physiological conditions [
      • Yang D.J.
      • Tran L.T.
      • Yoon S.G.
      • Seong J.K.
      • Shin D.M.
      • Choi Y.H.
      • et al.
      Primary cilia regulate adaptive responses to fasting.
      ]. They found aberrant adaptive responses to fasting and impaired neuroendocrine reflexes in the leptin response neuron-specific primary cilia-deficient mice. These findings demonstrate that the primary cilia are crucial neuronal components controlling our body's adaptation to fasting conditions and contribute to a better understanding of the pathogenesis of metabolic disorders, such as obesity.

      3.9 Reproductive biology

      Several studies published in "Metabolism" during the last three years have addressed the multi-factorial cross-talk between metabolism and reproductive function, illustrated also in various review articles [
      • Boutari C.
      • Pappas P.D.
      • Mintziori G.
      • Nigdelis M.P.
      • Athanasiadis L.
      • Goulis D.G.
      • et al.
      The effect of underweight on female and male reproduction.
      ,
      • Mintziori G.
      • Nigdelis M.P.
      • Mathew H.
      • Mousiolis A.
      • Goulis D.G.
      • Mantzoros C.S.
      The effect of excess body fat on female and male reproduction.
      ]. Androgen effects on metabolic parameters have been explored in both clinical and preclinical studies. Thus, Fernandez-Garcia et al. recently reported the results of a double-blind RCT showing the beneficial effects of testosterone supplementation on insulin resistance in a cohort of obese men with low testosterone levels [
      • Fernandez-Garcia J.C.
      • Barrios-Rodriguez R.
      • Asenjo-Plaza M.
      • Ramos-Molina B.
      • Molina-Vega M.
      • Guzman-Guzman A.
      • et al.
      Metformin, testosterone, or both in men with obesity and low testosterone: a double-blind, parallel-group, randomized controlled trial.
      ], while Kruse et al. documented the positive effects on skeletal muscle mass of long-term testosterone replacement therapy in elderly men with subnormal testosterone levels [
      • Kruse R.
      • Petersson S.J.
      • Christensen L.L.
      • Kristensen J.M.
      • Sabaratnam R.
      • Ortenblad N.
      • et al.
      Effect of long-term testosterone therapy on molecular regulators of skeletal muscle mass and fibre-type distribution in aging men with subnormal testosterone.
      ]. In addition, using a mouse model, Chen et al. provided novel evidence for a role of hepatic androgen receptor signaling in the control of blood glucose and body weight under physiological conditions [
      • Chen K.W.
      • Chen Y.S.
      • Chen P.J.
      • Yeh S.H.
      Androgen receptor functions in pericentral hepatocytes to decrease gluconeogenesis and avoid hyperglycemia and obesity in male mice.
      ]. In parallel, Meneyrol et al. have shown that depletion of ovarian secretion (including estrogen) in female rats causes hypothalamic inflammation and impairs glucose homeostasis that is partially mediated by hypothalamic de novo ceramide synthesis [
      • Meneyrol K.
      • Estevez-Salguero A.
      • Gonzalez-Garcia I.
      • Guitton J.
      • Taouis M.
      • Benomar Y.
      • et al.
      Ovarian insufficiency impairs glucose-stimulated insulin secretion through activation of hypothalamic de novo ceramide synthesis.
      ].
      In addition, evidence of novel mechanisms for the metabolic gating of reproductive function, especially in conditions of energy deficit, were recently presented in rodent models. Thus, Franssen et al. documented a role of AMPK signaling in gonadotropin-releasing hormone (GnRH) neurons in mediating part of the inhibitory effects of undernutrition to the reproductive axis [
      • Franssen D.
      • Barroso A.
      • Ruiz-Pino F.
      • Vazquez M.J.
      • Garcia-Galiano D.
      • Castellano J.M.
      • et al.
      AMP-activated protein kinase (AMPK) signaling in GnRH neurons links energy status and reproduction.
      ]. More recently, Perdices-Lopez et al. showed that G-protein coupled receptor kinase 2 (GRK2), also acting in GnRH neurons, participate in this phenomenon, likely by repressing kisspeptins signaling [
      • Perdices-Lopez C.
      • Avendano M.S.
      • Barroso A.
      • Gaytan F.
      • Ruiz-Pino F.
      • Vazquez M.J.
      • et al.
      Connecting nutritional deprivation and pubertal inhibition via GRK2-mediated repression of kisspeptin actions in GnRH neurons.
      ].
      Moreover, additional papers published recently in “Metabolism” addressed various facets of polycystic ovary syndrome (PCOS), a highly prevalent reproductive condition frequently linked to metabolic perturbations. Mechanistic studies, including the one by Chahal et al., suggested a pathogenic role of gonadotropin-induced glucose uptake and storage in granulosa cells in PCOS [
      • Chahal N.
      • Geethadevi A.
      • Kaur S.
      • Lakra R.
      • Nagendra A.
      • Shrivastav T.G.
      • et al.
      Direct impact of gonadotropins on glucose uptake and storage in preovulatory granulosa cells: implications in the pathogenesis of polycystic ovary syndrome.
      ]. Furthermore, Shen et al. showed that deregulation of the factors casitas B-lineage lymphoma protein-associated protein (CAP) and Lck/Yes-related novel protein (LYN), with capacity to influence insulin signaling cascades, in granulosa cells of PCOS women may contribute to the pathogenesis of this condition [
      • Shen H.
      • Xu X.
      • Fu Z.
      • Xu C.
      • Wang Y.
      The interactions of CAP and LYN with the insulin signaling transducer CBL play an important role in polycystic ovary syndrome.
      ]. In addition, Li et al. provided suggestive evidence for a role of ovarian 11β-hydroxysteroid dehydrogenases-1, the enzyme catalyzing the conversion of inactive cortisone to active cortisol, as pathogenic factor of PCOS, thus representing it as a potential target for its treatment [
      • Li X.
      • Hu S.
      • Zhu Q.
      • Yao G.
      • Yao J.
      • Li J.
      • et al.
      Addressing the role of 11beta-hydroxysteroid dehydrogenase type 1 in the development of polycystic ovary syndrome and the putative therapeutic effects of its selective inhibition in a preclinical model.
      ].

      3.10 Omics technologies

      Omics technologies have played an integral role in the advancement of our mechanistic understanding of metabolic disease. The wealth of knowledge that has been rapidly accumulating from the widespread use of these technologies and the increased capabilities they offer through the evolution of their methodologies, has led to the birth of multiple Omics fields, such as Genomics, Epigenomics, Proteomics and Metabolomics. The integration of these technologies in the implementation of basic and clinical research projects, and the recognition of their impact is reflected in the rapidly increasing number of research and review publications referring to different Omics tools and/or fields.
      Metabolism” has always been at the forefront of scientific developments [
      • Boutari C.
      • Bouzoni E.
      • Joshi A.
      • Stefanakis K.
      • Farr O.M.
      • Mantzoros C.S.
      Metabolism updates: new directions, techniques, and exciting research that is broadening the horizons.
      ]. The first publications on “Genomics” appeared in the early 2000s, with over 320 other papers published since. Most of these have been original research publications. Soon after, papers referring to Metabolomics, Proteomics and Epigenomics/Epigenetics were published in “Metabolism”, with over 100 papers referring to each of these fields published since. The term “Lipidomics” first appeared in “Metabolism” in 2012, and has been attracting considerable attention since, with >35 papers referring to Lipidomics to-date, most of which are original research articles. Following closely the emerging research trends, “Metabolism” has published manuscripts referring to “Metagenomics” and “Glycomics” since 2016 and 2018, respectively, and published the first review on Epitranscriptomics in metabolic disease in 2022 [
      • Sanoudou D.
      • Gkouskou K.K.
      • Eliopoulos A.G.
      • Mantzoros C.S.
      Epitranscriptomic challenges and promises in metabolic diseases.
      ]. These numbers mirror the relative contribution of the different Omics fields towards understanding and treating metabolic disease to date.
      Numerous highly impactful discoveries involving Omics approaches have been published in "Metabolism" over the years. Their contribution spans the full spectrum of basic-preclinical-translational-clinical research ranging from deciphering physiological biological mechanisms [
      • Luthold R.V.
      • Fernandes G.R.
      • Franco-de-Moraes A.C.
      • Folchetti L.G.
      • Ferreira S.R.
      Gut microbiota interactions with the immunomodulatory role of vitamin D in normal individuals.
      ,
      • Alfano R.
      • Chadeau-Hyam M.
      • Ghantous A.
      • Keski-Rahkonen P.
      • Chatzi L.
      • Perez A.E.
      • et al.
      A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism.
      ], to mapping of pathogenetic mechanisms [
      • Hamet P.
      • Tremblay J.
      Genetics and genomics of depression.
      ,
      • Matsuzawa-Nagata N.
      • Takamura T.
      • Ando H.
      • Nakamura S.
      • Kurita S.
      • Misu H.
      • et al.
      Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity.
      ,
      • Xie Z.
      • Li H.
      • Wang K.
      • Lin J.
      • Wang Q.
      • Zhao G.
      • et al.
      Analysis of transcriptome and metabolome profiles alterations in fatty liver induced by high-fat diet in rat.
      ,
      • Gouveia M.J.
      • Brindley P.J.
      • Santos L.L.
      • Correia da Costa J.M.
      • Gomes P.
      • Vale N.
      Mass spectrometry techniques in the survey of steroid metabolites as potential disease biomarkers: a review.
      ,
      • Simar D.
      • Versteyhe S.
      • Donkin I.
      • Liu J.
      • Hesson L.
      • Nylander V.
      • et al.
      DNA methylation is altered in B and NK lymphocytes in obese and type 2 diabetic human.
      ,
      • Dos Santos J.M.
      • Moreli M.L.
      • Tewari S.
      • Benite-Ribeiro S.A.
      The effect of exercise on skeletal muscle glucose uptake in type 2 diabetes: an epigenetic perspective.
      ,
      • Walle P.
      • Takkunen M.
      • Mannisto V.
      • Vaittinen M.
      • Lankinen M.
      • Karja V.
      • et al.
      Fatty acid metabolism is altered in non-alcoholic steatohepatitis independent of obesity.
      ,
      • Chang A.Y.
      • Lalia A.Z.
      • Jenkins G.D.
      • Dutta T.
      • Carter R.E.
      • Singh R.J.
      • et al.
      Combining a nontargeted and targeted metabolomics approach to identify metabolic pathways significantly altered in polycystic ovary syndrome.
      ,
      • Elouej S.
      • Beleza-Meireles A.
      • Caswell R.
      • Colclough K.
      • Ellard S.
      • Desvignes J.P.
      • et al.
      Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).
      ], identifying diagnostic [
      • Kalhan S.C.
      • Guo L.
      • Edmison J.
      • Dasarathy S.
      • McCullough A.J.
      • Hanson R.W.
      • et al.
      Plasma metabolomic profile in nonalcoholic fatty liver disease.
      ,
      • Perakakis N.
      • Polyzos S.A.
      • Yazdani A.
      • Sala-Vila A.
      • Kountouras J.
      • Anastasilakis A.D.
      • et al.
      Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: a proof of concept study.
      ,
      • Long M.T.
      • Gandhi S.
      • Loomba R.
      Advances in non-invasive biomarkers for the diagnosis and monitoring of non-alcoholic fatty liver disease.
      ], prognostic [
      • Batch B.C.
      • Shah S.H.
      • Newgard C.B.
      • Turer C.B.
      • Haynes C.
      • Bain J.R.
      • et al.
      Branched chain amino acids are novel biomarkers for discrimination of metabolic wellness.
      ,
      • Miller D.B.
      • O'Callaghan J.P.
      Biomarkers of Parkinson's disease: present and future.
      ], predictive [
      • Tremblay J.
      • Hamet P.
      Role of genomics on the path to personalized medicine.
      ,
      • del Rosario M.C.
      • Ossowski V.
      • Knowler W.C.
      • Bogardus C.
      • Baier L.J.
      • Hanson R.L.
      Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation.
      ,
      • Kalia M.
      • Costa E.S.J.
      Biomarkers of psychiatric diseases: current status and future prospects.
      ,
      • Kalia M.
      Biomarkers for personalized oncology: recent advances and future challenges.
      ,
      • Suvitaival T.
      • Bondia-Pons I.
      • Yetukuri L.
      • Poho P.
      • Nolan J.J.
      • Hyotylainen T.
      • et al.
      Lipidome as a predictive tool in progression to type 2 diabetes in finnish men.
      ] biomarkers, discovering therapeutic targets and evaluating the effects of different therapeutic approaches [
      • Kirk H.
      • Cefalu W.T.
      • Ribnicky D.
      • Liu Z.
      • Eilertsen K.J.
      Botanicals as epigenetic modulators for mechanisms contributing to development of metabolic syndrome.
      ,
      • Tsompanidis A.
      • Vafiadaki E.
      • Bluher S.
      • Kalozoumi G.
      • Sanoudou D.
      • Mantzoros C.S.
      Ciliary neurotrophic factor upregulates follistatin and Pak1, causes overexpression of muscle differentiation related genes and downregulation of established atrophy mediators in skeletal muscle.
      ,
      • Wang Y.
      • Shou J.W.
      • Li X.Y.
      • Zhao Z.X.
      • Fu J.
      • He C.Y.
      • et al.
      Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism.
      ,
      • Theofilatos D.
      • Fotakis P.
      • Valanti E.
      • Sanoudou D.
      • Zannis V.
      • Kardassis D.
      HDL-apoA-I induces the expression of angiopoietin like 4 (ANGPTL4) in endothelial cells via a PI3K/AKT/FOXO1 signaling pathway.
      ,
      • Perakakis N.
      • Yazdani A.
      • Karniadakis G.E.
      • Mantzoros C.
      Omics, big data and machine learning as tools to propel understanding of biological mechanisms and to discover novel diagnostics and therapeutics.
      ,
      • Perakakis N.
      • Stefanakis K.
      • Mantzoros C.S.
      The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease.
      ,
      • Valenzuela-Vallejo L.
      • Chrysafi P.
      • Bello-Ramos J.
      • Bsata S.
      • Mantzoros C.S.
      Circulating total and intact GDF-15 levels are not altered in response to weight loss induced by liraglutide or lorcaserin treatment in humans with obesity.
      ].
      Notable papers published over the past 3 years include the work of Castane et al., which combined semi-targeted lipidomics with artificial intelligence to search for serum biomarkers that could help combat the COVID-19 pandemic [
      • Castane H.
      • Iftimie S.
      • Baiges-Gaya G.
      • Rodriguez-Tomas E.
      • Jimenez-Franco A.
      • Lopez-Azcona A.F.
      • et al.
      Machine learning and semi-targeted lipidomics identify distinct serum lipid signatures in hospitalized COVID-19-positive and COVID-19-negative patients.
      ]. Specifically, liquid chromatography coupled to mass spectrometry was employed for the lipidome analysis of patients hospitalized for COVID-19 in comparison to patients hospitalized for other infectious/inflammatory diseases and healthy individuals. Using machine learning tools, the authors determined that many lipid alterations, including acylcarnitines, arachidonic acid and oxylipins, were shared between COVID-19 infection and other infectious/inflammatory diseases, whereas phosphatidylcholines and secondary bile acid-related changes were specifically altered only in the former. These findings point to lipidomic changes as likely implicated in COVID-19 pathophysiology and suggest a tentative role in clinical decision making. Moving towards the development of new treatments, Valanti et al. employed an elegant pharmacogenomics approach, coupled with in-depth in vitro (human coronary artery endothelial cell and the human EA.hy926 endothelial cell lines) and in vivo (apoE KO mice) studies to characterize the therapeutic potential of reconstituted HDL-apolipoproteinE3 (rHDL-apoE3) against atherosclerosis [
      • Valanti E.K.
      • Dalakoura-Karagkouni K.
      • Fotakis P.
      • Vafiadaki E.
      • Mantzoros C.S.
      • Chroni A.
      • et al.
      Reconstituted HDL-apoE3 promotes endothelial cell migration through ID1 and its downstream kinases ERK1/2, AKT and p38 MAPK.
      ]. The findings unveiled the significant enhancement of endothelial cell migration by rHDL-apoE3, and pinpointed the molecular pathways implicated, as well as the transcription factor ID1 as a mediator of these effects. Furthermore, administration of rHDL-apoE3 in apoE KO mice was shown to improve vascular permeability. This work provided novel insights into the rHDL-apoE3 functions, suggesting a clinical potential towards retarding the development of atherosclerosis. Omics approaches have also been successfully applied towards the improvement of disease management, as demonstrated by the pertinent study by Savikj et al. in patients with T2DM. In this study, men (age 45–68 years) with T2DM were enrolled in a high-intensity interval training (HIT) program that took place either in the morning or the afternoon [
      • Savikj M.
      • Stocks B.
      • Sato S.
      • Caidahl K.
      • Krook A.
      • Deshmukh A.S.
      • et al.
      Exercise timing influences multi-tissue metabolome and skeletal muscle proteome profiles in type 2 diabetic patients - a randomized crossover trial.
      ]. Proteomics and metabolomics were employed for the global unbiased characterization of the time-of-day effects of exercise in blood, skeletal muscle and adipose tissue. Their findings determined that there is a diurnal component in the metabolomic and proteomic response to exercise in men with T2DM, with circulating carbohydrates being higher after morning vs. afternoon HIT, while afternoon HIT increased skeletal muscle lipids and mitochondrial content compared to morning training. This knowledge is valuable towards the establishment of “finely-tuned” training recommendations for individuals with metabolic disease, the improvement of their quality of life and ultimately the prevention of disease progression.

      4. Concluding remarks

      It is certainly satisfying to collectively consider the contributions that “Metabolism” has made to the field, both recent and past. The realization that the journal is “seventy years young and growing” sets the stage for future challenges and goals. We are indebted to all those who have been, and continue to be, involved in this exciting journey as we move on and up.

      Funding

      No sources of financial support for this manuscript.

      Declaration of competing interest

      SAP: Associate Editor of “Metabolism”.
      MAH: Associate Editor of “Metabolism”.
      GEF: Associate Editor of “Metabolism”.
      LG: Associate Editor of “Metabolism”.
      YBK: Associate Editor of “Metabolism”.
      SL: Associate Editor of “Metabolism”.
      HM: Associate Editor of “Metabolism”.
      GM: Associate Editor of “Metabolism”.
      DS: Associate Editor of “Metabolism”.
      MTS: Associate Editor of “Metabolism”.
      CSM: Editor-in-chief of “Metabolism”; CSM reports grants, personal fees and other from Coherus Inc., grants, personal fees and other from Novo Nordisk, personal fees and non-financial support from Ansh, non-financial in kind support from LabCorp, grants from Merck, personal fees and non-financial support from Aegerion, personal fees and non-financial support from California Walnut Commission, personal fees from Genfit, Regeneron, Amgen, Corcept, personal fees from Intercept, meals through scientific conference organizers from Amarin, Astra Zeneca, Jansen, Boehringer Ingelheim, personal fees and other from CardioMetabolic Health Conference - The Metabolic Institute of America: all outside this work.

      References

        • Soskin S.
        Editorial: resignation of editor-in-chief.
        Metabolism. 1957; 6: 403
        • Duncan G.G.
        Editorial.
        Metabolism. 1958; 7: 1-2
        • Field J.B.
        Editorial.
        Metabolism. 1970; 19: 91-92
        • Field J.B.
        Passing the torch.
        Metabolism. 2010; 59: 1393
        • Mantzoros C.S.
        Accepting the torch.
        Metabolism. 2010; 59: 1394-1395
        • Duncan G.G.
        An adieu.
        Metabolism. 1970; 18: 975-976
        • Miller A.
        • Fain J.N.
        • Bray G.A.
        Tributes to retiring editor-in-chief of metabolism, James B. Field.
        Metabolism. 2010; 59: 1083
        • Polyzos S.A.
        • Mantzoros C.S.
        Sixty-six years of metabolism, clinical and experimental: the journey of a journal and opportunities and challenges looking ahead.
        Metabolism. 2018; 78: A4-A9
        • Chooi Y.C.
        • Ding C.
        • Magkos F.
        The epidemiology of obesity.
        Metabolism. 2019; 92: 6-10
        • Avgerinos K.I.
        • Spyrou N.
        • Mantzoros C.S.
        • Dalamaga M.
        Obesity and cancer risk: emerging biological mechanisms and perspectives.
        Metabolism. 2019; 92: 121-135
        • Polyzos S.A.
        • Kountouras J.
        • Mantzoros C.S.
        Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics.
        Metabolism. 2019; 92: 82-97
        • Koliaki C.
        • Liatis S.
        • Kokkinos A.
        Obesity and cardiovascular disease: revisiting an old relationship.
        Metabolism. 2019; 92: 98-107
        • Palaiodimos L.
        • Kokkinidis D.G.
        • Li W.
        • Karamanis D.
        • Ognibene J.
        • Arora S.
        Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York.
        Metabolism. 2020; 108154262
        • Chen X.
        • Li X.
        • Zhang W.
        • He J.
        • Xu B.
        • Lei B.
        • et al.
        Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-κB pathway.
        Metabolism. 2018; 83: 256-270
        • Watanabe M.
        • Caruso D.
        • Tuccinardi D.
        • Risi R.
        • Zerunian M.
        • Polici M.
        • et al.
        Visceral fat shows the strongest association with the need of intensive care in patients with COVID-19.
        Metabolism. 2020; 111154319
        • Petersen A.
        • Bressem K.
        • Albrecht J.
        • Thieß H.M.
        • Vahldiek J.
        • Hamm B.
        • et al.
        The role of visceral adiposity in the severity of COVID-19: highlights from a unicenter cross-sectional pilot study in Germany.
        Metabolism. 2020; 110154317
        • Huang Y.
        • Lu Y.
        • Huang Y.M.
        • Wang M.
        • Ling W.
        • Sui Y.
        • et al.
        Obesity in patients with COVID-19: a systematic review and meta-analysis.
        Metabolism. 2020; 113154378
        • Zhu Z.
        • Hasegawa K.
        • Ma B.
        • Fujiogi M.
        • Camargo Jr., C.A.
        • Liang L.
        Association of obesity and its genetic predisposition with the risk of severe COVID-19: analysis of population-based cohort data.
        Metabolism. 2020; 112154345
        • Favre G.
        • Legueult K.
        • Pradier C.
        • Raffaelli C.
        • Ichai C.
        • Iannelli A.
        • et al.
        Visceral fat is associated to the severity of COVID-19.
        Metabolism. 2021; 115154440
        • Freuer D.
        • Linseisen J.
        • Meisinger C.
        Impact of body composition on COVID-19 susceptibility and severity: a two-sample multivariable mendelian randomization study.
        Metabolism. 2021; 118154732
        • Wang Y.
        • Xu J.
        • Wang Y.
        • Hou H.
        • Feng H.
        • Yang H.
        An updated meta-analysis on the relationship between obesity and COVID-19 mortality.
        Metabolism. 2021; 122154820
        • Kim N.H.
        • Kim K.J.
        • Choi J.
        • Kim S.G.
        Metabolically unhealthy individuals, either with obesity or not, have a higher risk of critical coronavirus disease 2019 outcomes than metabolically healthy individuals without obesity.
        Metabolism. 2022; 128154894
        • Du Y.
        • Lv Y.
        • Zha W.
        • Zhou N.
        • Hong X.
        Association of body mass index (BMI) with critical COVID-19 and in-hospital mortality: a dose-response meta-analysis.
        Metabolism. 2021; 117154373
        • Bassatne A.
        • Basbous M.
        • Chakhtoura M.
        • El Zein O.
        • Rahme M.
        • El-Hajj Fuleihan G.
        The link between COVID-19 and VItamin D (VIVID): a systematic review and meta-analysis.
        Metabolism. 2021; 119154753
        • Smolders J.
        • van den Ouweland J.
        • Geven C.
        • Pickkers P.
        • Kox M.
        Letter to the editor: vitamin D deficiency in COVID-19: mixing up cause and consequence.
        Metabolism. 2021; 115154434
        • Blomdahl J.
        • Nasr P.
        • Ekstedt M.
        • Kechagias S.
        Moderate alcohol consumption is associated with advanced fibrosis in non-alcoholic fatty liver disease and shows a synergistic effect with type 2 diabetes mellitus.
        Metabolism. 2021; 115154439
        • Ciardullo S.
        • Perseghin G.
        Statin use is associated with lower prevalence of advanced liver fibrosis in patients with type 2 diabetes.
        Metabolism. 2021; 121154752
        • Athyros V.G.
        • Alexandrides T.K.
        • Bilianou H.
        • Cholongitas E.
        • Doumas M.
        • Ganotakis E.S.
        The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement.
        Metabolism. 2017; 71: 17-32
        • Chung G.E.
        • Cho E.J.
        • Yoon J.W.
        • Yoo J.J.
        • Chang Y.
        • Cho Y.
        • et al.
        Nonalcoholic fatty liver disease increases the risk of diabetes in young adults: a nationwide population-based study in Korea.
        Metabolism. 2021; 123154866
        • Liu Z.
        • Suo C.
        • Fan H.
        • Zhang T.
        • Jin L.
        • Chen X.
        Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases.
        Metabolism. 2022; 135155270
        • Peng H.
        • Wang S.
        • Wang M.
        • Ye Y.
        • Xue E.
        • Chen X.
        • et al.
        Nonalcoholic fatty liver disease and cardiovascular diseases: a mendelian randomization study.
        Metabolism. 2022; 133155220
        • Liu Z.
        • Lin C.
        • Suo C.
        • Zhao R.
        • Jin L.
        • Zhang T.
        • et al.
        Metabolic dysfunction-associated fatty liver disease and the risk of 24 specific cancers.
        Metabolism. 2022; 127154955
        • Chung G.E.
        • Jeong S.M.
        • Cho E.J.
        • Yoo J.J.
        • Cho Y.
        • Lee K.N.
        • et al.
        Association of fatty liver index with all-cause and disease-specific mortality: a nationwide cohort study.
        Metabolism. 2022; 133155222
        • Baumann A.
        • Burger K.
        • Brandt A.
        • Staltner R.
        • Jung F.
        • Rajcic D.
        • et al.
        GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease.
        Metabolism. 2022; 133155233
        • Kouvari M.
        • Chrysohoou C.
        • Skoumas J.
        • Pitsavos C.
        • Panagiotakos D.B.
        • Mantzoros C.S.
        • et al.
        The presence of NAFLD influences the transition of metabolically healthy to metabolically unhealthy obesity and the ten-year cardiovascular disease risk: a population-based cohort study.
        Metabolism. 2022; 128154893
        • Nimer N.
        • Choucair I.
        • Wang Z.
        • Nemet I.
        • Li L.
        • Gukasyan J.
        • et al.
        Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression.
        Metabolism. 2021; 116154457
        • Longo M.
        • Meroni M.
        • Paolini E.
        • Macchi C.
        • Dongiovanni P.
        Mitochondrial dynamics and nonalcoholic fatty liver disease (NAFLD): new perspectives for a fairy-tale ending?.
        Metabolism. 2021; 117154708
        • Nawrot M.
        • Peschard S.
        • Lestavel S.
        • Staels B.
        Intestine-liver crosstalk in type 2 diabetes and non-alcoholic fatty liver disease.
        Metabolism. 2021; 123154844
        • Pessoa J.
        • Teixeira J.
        Cytoskeleton alterations in non-alcoholic fatty liver disease.
        Metabolism. 2022; 128155115
        • Zhu J.Y.
        • Chen M.
        • Mu W.J.
        • Luo H.Y.
        • Guo L.
        Higd1a facilitates exercise-mediated alleviation of fatty liver in diet-induced obese mice.
        Metabolism. 2022; 134155241
        • Sun D.Q.
        • Jin Y.
        • Wang T.Y.
        • Zheng K.I.
        • Rios R.S.
        • Zhang H.Y.
        • et al.
        MAFLD and risk of CKD.
        Metabolism. 2021; 115154433
        • Anguita-Ruiz A.
        • Mendez-Gutierrez A.
        • Ruperez A.I.
        • Leis R.
        • Bueno G.
        • Gil-Campos M.
        • et al.
        The protein S100A4 as a novel marker of insulin resistance in prepubertal and pubertal children with obesity.
        Metabolism. 2020; 105154187
        • Fukuhara S.
        • Yasukawa K.
        • Sato M.
        • Ikeda H.
        • Inoguchi Y.
        • Etoh T.
        • et al.
        Clinical usefulness of human serum nonmercaptalbumin to mercaptalbumin ratio as a biomarker for diabetic complications and disability in activities of daily living in elderly patients with diabetes.
        Metabolism. 2020; 103153995
        • van Son J.
        • Stam S.P.
        • Gomes-Neto A.W.
        • Oste M.C.J.
        • Blokzijl H.
        • van den Berg A.P.
        • et al.
        Post-transplant obesity impacts long-term survival after liver transplantation.
        Metabolism. 2020; 106154204
        • Polyzos S.A.
        • Kountouras J.
        • Shields K.
        • Mantzoros C.S.
        Irisin: a renaissance in metabolism?.
        Metabolism. 2013; 62: 1037-1044
        • Frühbeck G.
        • Fernández-Quintana B.
        • Paniagua M.
        • Hernández-Pardos A.W.
        • Valentí V.
        • Moncada R.
        • et al.
        FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes.
        Metabolism. 2020; 108154261
        • Park J.
        • Seo Y.G.
        • Paek Y.J.
        • Song H.J.
        • Park K.H.
        • Noh H.M.
        Effect of alternate-day fasting on obesity and cardiometabolic risk: a systematic review and meta-analysis.
        Metabolism. 2020; 111154336
        • Borges D.O.
        • Patarrão R.S.
        • Ribeiro R.T.
        • de Oliveira R.M.
        • Duarte N.
        • Belew G.D.
        • et al.
        Loss of postprandial insulin clearance control by insulin-degrading enzyme drives dysmetabolism traits.
        Metabolism. 2021; 118154735
        • Wu M.
        • Yang Z.
        • Zhang C.
        • Shi Y.
        • Han W.
        • Song S.
        • et al.
        Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy.
        Metabolism. 2021; 118154748
        • Loretelli C.
        • Rocchio F.
        • D'Addio F.
        • Ben Nasr M.
        • Castillo-Leon E.
        • Dellepiane S.
        • et al.
        The IL-8-CXCR1/2 axis contributes to diabetic kidney disease.
        Metabolism. 2021; 121154804
        • Zhang Y.
        • Cai Y.
        • Zhang H.
        • Zhang J.
        • Zeng Y.
        • Fan C.
        • et al.
        Brown adipose tissue transplantation ameliorates diabetic nephropathy through the miR-30b pathway by targeting Runx1.
        Metabolism. 2021; 125154916
        • Yang T.
        • Heng C.
        • Zhou Y.
        • Hu Y.
        • Chen S.
        • Wang H.
        • et al.
        Targeting mammalian serine/threonine-protein kinase 4 through yes-associated protein/TEA domain transcription factor-mediated epithelial-mesenchymal transition ameliorates diabetic nephropathy orchestrated renal fibrosis.
        Metabolism. 2020; 108154258
        • Yang T.
        • Heng C.
        • Zhou Y.
        • Hu Y.
        • Chen S.
        • Wang H.
        • et al.
        Corrigendum to 'Targeting mammalian serine/threonine-protein kinase 4 through yes-associated protein/TEA domain transcription factor-mediated epithelial-mesenchymal transition ameliorates diabetic nephropathy orchestrated renal fibrosis [Metabolism clinical and experimental 108 (2020) 154258].
        Metabolism. 2022; 130154963
        • Luo Q.
        • Liang W.
        • Zhang Z.
        • Zhu Z.
        • Chen Z.
        • Hu J.
        • et al.
        Compromised glycolysis contributes to foot process fusion of podocytes in diabetic kidney disease: role of ornithine catabolism.
        Metabolism. 2022; 134155245
        • Wilson C.
        • Zhang X.
        • Lee M.D.
        • MacDonald M.
        • Heathcote H.R.
        • Alorfi N.M.N.
        • et al.
        Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity.
        Metabolism. 2020; 111154340
        • Mishra R.C.
        • Kyle B.D.
        • Kendrick D.J.
        • Svystonyuk D.
        • Kieser T.M.
        • Fedak P.W.M.
        • et al.
        KCa channel activation normalizes endothelial function in type 2 diabetic resistance arteries by improving intracellular Ca(2+) mobilization.
        Metabolism. 2021; 114154390
        • Sowers J.R.
        • Habibi J.
        • Jia G.
        • Bostick B.
        • Manrique-Acevedo C.
        • Lastra G.
        • et al.
        Endothelial sodium channel activation promotes cardiac stiffness and diastolic dysfunction in Western diet fed female mice.
        Metabolism. 2020; 109154223
        • Ong K.L.
        • McClelland R.L.
        • Allison M.A.
        • Cushman M.
        • Garg P.K.
        • Tsai M.Y.
        • et al.
        Lipoprotein (a) and coronary artery calcification: prospective study assessing interactions with other risk factors.
        Metabolism. 2021; 116154706
        • Phan K.
        • Schiller I.
        • Dendukuri N.
        • Gomez Y.H.
        • Gorgui J.
        • El-Messidi A.
        • et al.
        A longitudinal analysis of arterial stiffness and wave reflection in preeclampsia: identification of changepoints.
        Metabolism. 2021; 120154794
        • Uddin G.M.
        • Karwi Q.G.
        • Pherwani S.
        • Gopal K.
        • Wagg C.S.
        • Biswas D.
        • et al.
        Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart.
        Metabolism. 2021; 124154871
        • Monzo L.
        • Sedlacek K.
        • Hromanikova K.
        • Tomanova L.
        • Borlaug B.A.
        • Jabor A.
        • et al.
        Myocardial ketone body utilization in patients with heart failure: the impact of oral ketone ester.
        Metabolism. 2021; 115154452
        • Luong T.V.
        • Pedersen M.G.B.
        • Kjærulff M.
        • Madsen S.
        • Lauritsen K.M.
        • Tolbod L.P.
        • et al.
        Ischemic heart failure mortality is not predicted by cardiac insulin resistance but by diabetes per se and coronary flow reserve: a retrospective dynamic cardiac (18)F-FDG PET study.
        Metabolism. 2021; 123154862
        • Liu H.
        • Sridhar V.S.
        • Boulet J.
        • Dharia A.
        • Khan A.
        • Lawler P.R.
        • et al.
        Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease.
        Metabolism. 2022; 126154918
        • Sachinidis A.
        • Nikolic D.
        • Stoian A.P.
        • Papanas N.
        • Tarar O.
        • Rizvi A.A.
        • et al.
        Cardiovascular outcomes trials with incretin-based medications: a critical review of data available on GLP-1 receptor agonists and DPP-4 inhibitors.
        Metabolism. 2020; 111154343
        • Triggle C.R.
        • Mohammed I.
        • Bshesh K.
        • Marei I.
        • Ye K.
        • Ding H.
        • et al.
        Metformin: is it a drug for all reasons and diseases?.
        Metabolism. 2022; 133155223
        • Schernthaner G.
        • Brand K.
        • Bailey C.J.
        Metformin and the heart: update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure.
        Metabolism. 2022; 130155160
        • Natali A.
        • Nesti L.
        Vascular effects of insulin.
        Metabolism. 2021; 124154891
        • Sardu C.
        • Massimo Massetti M.
        • Rambaldi P.
        • Gatta G.
        • Cappabianca S.
        • Sasso F.C.
        • et al.
        SGLT2-inhibitors reduce the cardiac autonomic neuropathy dysfunction and vaso-vagal syncope recurrence in patients with type 2 diabetes mellitus: the SCAN study.
        Metabolism. 2022; https://doi.org/10.1016/j.metabol.2022.155243:155243
        • Frost H.M.
        • Schönau E.
        The, "Muscle-bone Unit" in children and adolescents: a 2000 overview.
        J Pediatr Endocrinol Metab. 2000; 13: 571-590
        • Beresford J.N.
        • Bennett J.H.
        • Devlin C.
        • Leboy P.S.
        • Owen M.E.
        Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures.
        J Cell Sci. 1992; 102: 341-351
        • Kirk B.
        • Feehan J.
        • Lombardi G.
        • Duque G.
        Muscle, bone, and fat crosstalk: the biological role of myokines, osteokines, and adipokines.
        Curr Osteoporos Rep. 2020; 18: 388-400
        • Anastasilakis A.D.
        • Polyzos S.A.
        • Makras P.
        • Douni E.
        • Mantzoros C.S.
        Irisin: good or bad for the bone? A new path forward after the reported discovery of irisin receptor?.
        Metabolism. 2019; 93: 100-102
        • Lee J.
        • Han K.
        • Park S.H.
        • Kim M.K.
        • Lim D.J.
        • Yoon K.H.
        • et al.
        Associations of variability in body weight and glucose levels with the risk of hip fracture in people with diabetes.
        Metabolism. 2022; 129155135
        • Tian L.
        • Xiao H.
        • Li M.
        • Wu X.
        • Xie Y.
        • Zhou J.
        • et al.
        A novel Sprouty4-ERK1/2-Wnt/β-catenin regulatory loop in marrow stromal progenitor cells controls osteogenic and adipogenic differentiation.
        Metabolism. 2020; 105154189
        • Seok J.W.
        • Kim D.
        • Yoon B.K.
        • Lee Y.
        • Kim H.J.
        • Hwang N.
        • et al.
        Dexras1 plays a pivotal role in maintaining the equilibrium between adipogenesis and osteogenesis.
        Metabolism. 2020; 108154250
        • Jensen G.S.
        • Leon-Palmer N.E.
        • Townsend K.L.
        Bone morphogenetic proteins (BMPs) in the central regulation of energy balance and adult neural plasticity.
        Metabolism. 2021; 123154837
        • Christakos S.
        • Li S.
        • De La Cruz J.
        • Bikle D.D.
        New developments in our understanding of vitamin metabolism, action and treatment.
        Metabolism. 2019; 98: 112-120
        • Bassatne A.
        • Chakhtoura M.
        • Saad R.
        • Fuleihan G.E.
        Vitamin D supplementation in obesity and during weight loss: a review of randomized controlled trials.
        Metabolism. 2019; 92: 193-205
        • Xu L.
        • Chen Y.
        • Nagashimada M.
        • Ni Y.
        • Zhuge F.
        • Chen G.
        • et al.
        CC chemokine ligand 3 deficiency ameliorates diet-induced steatohepatitis by regulating liver macrophage recruitment and M1/M2 status in mice.
        Metabolism. 2021; 125154914
        • Wang X.
        • Chen S.
        • He J.
        • Chen W.
        • Ding Y.
        • Huang J.
        • et al.
        Histone methyltransferases G9a mediated lipid-induced M1 macrophage polarization through negatively regulating CD36.
        Metabolism. 2021; 114154404
        • Van Campenhout S.
        • Tilleman L.
        • Lefere S.
        • Vandierendonck A.
        • Raevens S.
        • Verhelst X.
        • et al.
        Myeloid-specific IRE1alpha deletion reduces tumour development in a diabetic, non-alcoholic steatohepatitis-induced hepatocellular carcinoma mouse model.
        Metabolism. 2020; 107154220
        • Hu X.
        • Jia X.
        • Xu C.
        • Wei Y.
        • Wang Z.
        • Liu G.
        • et al.
        Downregulation of NK cell activities in apolipoprotein C-III-induced hyperlipidemia resulting from lipid-induced metabolic reprogramming and crosstalk with lipid-laden dendritic cells.
        Metabolism. 2021; 120154800
        • Metz L.
        • Isacco L.
        • Redman L.M.
        Effect of oral contraceptives on energy balance in women: a review of current knowledge and potential cellular mechanisms.
        Metabolism. 2022; 126154919
        • van Galen K.A.
        • Booij J.
        • Schrantee A.
        • Adriaanse S.M.
        • Unmehopa U.A.
        • Fliers E.
        • et al.
        The response to prolonged fasting in hypothalamic serotonin transporter availability is blunted in obesity.
        Metabolism. 2021; 123154839
        • Gavini C.K.
        • Cook T.M.
        • Rademacher D.J.
        • Mansuy-Aubert V.
        Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance.
        Metabolism. 2020; 102153990
        • Yang D.J.
        • Tran L.T.
        • Yoon S.G.
        • Seong J.K.
        • Shin D.M.
        • Choi Y.H.
        • et al.
        Primary cilia regulate adaptive responses to fasting.
        Metabolism. 2022; 135155273
        • Boutari C.
        • Pappas P.D.
        • Mintziori G.
        • Nigdelis M.P.
        • Athanasiadis L.
        • Goulis D.G.
        • et al.
        The effect of underweight on female and male reproduction.
        Metabolism. 2020; 107154229
        • Mintziori G.
        • Nigdelis M.P.
        • Mathew H.
        • Mousiolis A.
        • Goulis D.G.
        • Mantzoros C.S.
        The effect of excess body fat on female and male reproduction.
        Metabolism. 2020; 107154193
        • Fernandez-Garcia J.C.
        • Barrios-Rodriguez R.
        • Asenjo-Plaza M.
        • Ramos-Molina B.
        • Molina-Vega M.
        • Guzman-Guzman A.
        • et al.
        Metformin, testosterone, or both in men with obesity and low testosterone: a double-blind, parallel-group, randomized controlled trial.
        Metabolism. 2022; 136155290
        • Kruse R.
        • Petersson S.J.
        • Christensen L.L.
        • Kristensen J.M.
        • Sabaratnam R.
        • Ortenblad N.
        • et al.
        Effect of long-term testosterone therapy on molecular regulators of skeletal muscle mass and fibre-type distribution in aging men with subnormal testosterone.
        Metabolism. 2020; 112154347
        • Chen K.W.
        • Chen Y.S.
        • Chen P.J.
        • Yeh S.H.
        Androgen receptor functions in pericentral hepatocytes to decrease gluconeogenesis and avoid hyperglycemia and obesity in male mice.
        Metabolism. 2022; 135155269
        • Meneyrol K.
        • Estevez-Salguero A.
        • Gonzalez-Garcia I.
        • Guitton J.
        • Taouis M.
        • Benomar Y.
        • et al.
        Ovarian insufficiency impairs glucose-stimulated insulin secretion through activation of hypothalamic de novo ceramide synthesis.
        Metabolism. 2021; 123154846
        • Franssen D.
        • Barroso A.
        • Ruiz-Pino F.
        • Vazquez M.J.
        • Garcia-Galiano D.
        • Castellano J.M.
        • et al.
        AMP-activated protein kinase (AMPK) signaling in GnRH neurons links energy status and reproduction.
        Metabolism. 2021; 115154460
        • Perdices-Lopez C.
        • Avendano M.S.
        • Barroso A.
        • Gaytan F.
        • Ruiz-Pino F.
        • Vazquez M.J.
        • et al.
        Connecting nutritional deprivation and pubertal inhibition via GRK2-mediated repression of kisspeptin actions in GnRH neurons.
        Metabolism. 2022; 129155141
        • Chahal N.
        • Geethadevi A.
        • Kaur S.
        • Lakra R.
        • Nagendra A.
        • Shrivastav T.G.
        • et al.
        Direct impact of gonadotropins on glucose uptake and storage in preovulatory granulosa cells: implications in the pathogenesis of polycystic ovary syndrome.
        Metabolism. 2021; 115154458
        • Shen H.
        • Xu X.
        • Fu Z.
        • Xu C.
        • Wang Y.
        The interactions of CAP and LYN with the insulin signaling transducer CBL play an important role in polycystic ovary syndrome.
        Metabolism. 2022; 131155164
        • Li X.
        • Hu S.
        • Zhu Q.
        • Yao G.
        • Yao J.
        • Li J.
        • et al.
        Addressing the role of 11beta-hydroxysteroid dehydrogenase type 1 in the development of polycystic ovary syndrome and the putative therapeutic effects of its selective inhibition in a preclinical model.
        Metabolism. 2021; 119154749
        • Boutari C.
        • Bouzoni E.
        • Joshi A.
        • Stefanakis K.
        • Farr O.M.
        • Mantzoros C.S.
        Metabolism updates: new directions, techniques, and exciting research that is broadening the horizons.
        Metabolism. 2020; 102154009
        • Sanoudou D.
        • Gkouskou K.K.
        • Eliopoulos A.G.
        • Mantzoros C.S.
        Epitranscriptomic challenges and promises in metabolic diseases.
        Metabolism. 2022; 132155219
        • Luthold R.V.
        • Fernandes G.R.
        • Franco-de-Moraes A.C.
        • Folchetti L.G.
        • Ferreira S.R.
        Gut microbiota interactions with the immunomodulatory role of vitamin D in normal individuals.
        Metabolism. 2017; 69: 76-86
        • Alfano R.
        • Chadeau-Hyam M.
        • Ghantous A.
        • Keski-Rahkonen P.
        • Chatzi L.
        • Perez A.E.
        • et al.
        A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism.
        Metabolism. 2020; 110154292
        • Hamet P.
        • Tremblay J.
        Genetics and genomics of depression.
        Metabolism. 2005; 54: 10-15
        • Matsuzawa-Nagata N.
        • Takamura T.
        • Ando H.
        • Nakamura S.
        • Kurita S.
        • Misu H.
        • et al.
        Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity.
        Metabolism. 2008; 57: 1071-1077
        • Xie Z.
        • Li H.
        • Wang K.
        • Lin J.
        • Wang Q.
        • Zhao G.
        • et al.
        Analysis of transcriptome and metabolome profiles alterations in fatty liver induced by high-fat diet in rat.
        Metabolism. 2010; 59: 554-560
        • Gouveia M.J.
        • Brindley P.J.
        • Santos L.L.
        • Correia da Costa J.M.
        • Gomes P.
        • Vale N.
        Mass spectrometry techniques in the survey of steroid metabolites as potential disease biomarkers: a review.
        Metabolism. 2013; 62: 1206-1217
        • Simar D.
        • Versteyhe S.
        • Donkin I.
        • Liu J.
        • Hesson L.
        • Nylander V.
        • et al.
        DNA methylation is altered in B and NK lymphocytes in obese and type 2 diabetic human.
        Metabolism. 2014; 63: 1188-1197
        • Dos Santos J.M.
        • Moreli M.L.
        • Tewari S.
        • Benite-Ribeiro S.A.
        The effect of exercise on skeletal muscle glucose uptake in type 2 diabetes: an epigenetic perspective.
        Metabolism. 2015; 64: 1619-1628
        • Walle P.
        • Takkunen M.
        • Mannisto V.
        • Vaittinen M.
        • Lankinen M.
        • Karja V.
        • et al.
        Fatty acid metabolism is altered in non-alcoholic steatohepatitis independent of obesity.
        Metabolism. 2016; 65: 655-666
        • Chang A.Y.
        • Lalia A.Z.
        • Jenkins G.D.
        • Dutta T.
        • Carter R.E.
        • Singh R.J.
        • et al.
        Combining a nontargeted and targeted metabolomics approach to identify metabolic pathways significantly altered in polycystic ovary syndrome.
        Metabolism. 2017; 71: 52-63
        • Elouej S.
        • Beleza-Meireles A.
        • Caswell R.
        • Colclough K.
        • Ellard S.
        • Desvignes J.P.
        • et al.
        Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).
        Metabolism. 2017; 71: 213-225
        • Kalhan S.C.
        • Guo L.
        • Edmison J.
        • Dasarathy S.
        • McCullough A.J.
        • Hanson R.W.
        • et al.
        Plasma metabolomic profile in nonalcoholic fatty liver disease.
        Metabolism. 2011; 60: 404-413
        • Perakakis N.
        • Polyzos S.A.
        • Yazdani A.
        • Sala-Vila A.
        • Kountouras J.
        • Anastasilakis A.D.
        • et al.
        Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: a proof of concept study.
        Metabolism. 2019; 101154005
        • Long M.T.
        • Gandhi S.
        • Loomba R.
        Advances in non-invasive biomarkers for the diagnosis and monitoring of non-alcoholic fatty liver disease.
        Metabolism. 2020; 111S154259
        • Batch B.C.
        • Shah S.H.
        • Newgard C.B.
        • Turer C.B.
        • Haynes C.
        • Bain J.R.
        • et al.
        Branched chain amino acids are novel biomarkers for discrimination of metabolic wellness.
        Metabolism. 2013; 62: 961-969
        • Miller D.B.
        • O'Callaghan J.P.
        Biomarkers of Parkinson's disease: present and future.
        Metabolism. 2015; 64: S40-S46
        • Tremblay J.
        • Hamet P.
        Role of genomics on the path to personalized medicine.
        Metabolism. 2013; 62: S2-S5
        • del Rosario M.C.
        • Ossowski V.
        • Knowler W.C.
        • Bogardus C.
        • Baier L.J.
        • Hanson R.L.
        Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation.
        Metabolism. 2014; 63: 654-660
        • Kalia M.
        • Costa E.S.J.
        Biomarkers of psychiatric diseases: current status and future prospects.
        Metabolism. 2015; 64: S11-S15
        • Kalia M.
        Biomarkers for personalized oncology: recent advances and future challenges.
        Metabolism. 2015; 64: S16-S21
        • Suvitaival T.
        • Bondia-Pons I.
        • Yetukuri L.
        • Poho P.
        • Nolan J.J.
        • Hyotylainen T.
        • et al.
        Lipidome as a predictive tool in progression to type 2 diabetes in finnish men.
        Metabolism. 2018; 78: 1-12
        • Kirk H.
        • Cefalu W.T.
        • Ribnicky D.
        • Liu Z.
        • Eilertsen K.J.
        Botanicals as epigenetic modulators for mechanisms contributing to development of metabolic syndrome.
        Metabolism. 2008; 57: S16-S23
        • Tsompanidis A.
        • Vafiadaki E.
        • Bluher S.
        • Kalozoumi G.
        • Sanoudou D.
        • Mantzoros C.S.
        Ciliary neurotrophic factor upregulates follistatin and Pak1, causes overexpression of muscle differentiation related genes and downregulation of established atrophy mediators in skeletal muscle.
        Metabolism. 2016; 65: 915-925
        • Wang Y.
        • Shou J.W.
        • Li X.Y.
        • Zhao Z.X.
        • Fu J.
        • He C.Y.
        • et al.
        Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism.
        Metabolism. 2017; 70: 72-84
        • Theofilatos D.
        • Fotakis P.
        • Valanti E.
        • Sanoudou D.
        • Zannis V.
        • Kardassis D.
        HDL-apoA-I induces the expression of angiopoietin like 4 (ANGPTL4) in endothelial cells via a PI3K/AKT/FOXO1 signaling pathway.
        Metabolism. 2018; 87: 36-47
        • Perakakis N.
        • Yazdani A.
        • Karniadakis G.E.
        • Mantzoros C.
        Omics, big data and machine learning as tools to propel understanding of biological mechanisms and to discover novel diagnostics and therapeutics.
        Metabolism. 2018; 87: A1-A9
        • Perakakis N.
        • Stefanakis K.
        • Mantzoros C.S.
        The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease.
        Metabolism. 2020; 111S154320
        • Valenzuela-Vallejo L.
        • Chrysafi P.
        • Bello-Ramos J.
        • Bsata S.
        • Mantzoros C.S.
        Circulating total and intact GDF-15 levels are not altered in response to weight loss induced by liraglutide or lorcaserin treatment in humans with obesity.
        Metabolism. 2022; 133155237