Highlights
- •We investigated the effect of ANGPTL8 on glucose homeostasis in diabetic mice.
- •ANGPTL8 decreases fasting blood glucose levels and improves glucose tolerance.
- •ANGPTL8 overexpression inhibits gluconeogenesis through AKT signaling.
- •ANGPTL8 expression could be a factor for inhibiting hepatic gluconeogenesis.
- •The mechanism may be targeted for prevention and treatment of type 2 diabetes.
Abstract
Background & aims
Angiopoietin-like protein 8 (ANGPTL8) is a 198 amino-acid long, novel secreted protein
that is mainly expressed in the liver and brown adipose tissues. At present, evidence
supporting the involvement of ANGPTL8 in the regulation of glucose metabolism is inconclusive,
along with its function in the liver. Previous studies mainly focused on the effect
of ANGPTL8 on glucose metabolism in non-diabetic mice, and few relevant studies in
diabetic mice exist. Therefore, this study aimed to investigate the role of ANGPTL8
on glucose homeostasis and elucidate the underlying mechanisms in diabetic mice.
Methods
db/db diabetic and high-fat diet/streptozotocin-induced diabetic mice were injected
with adenovirus expressing ANGPTL8 through the tail vein. Blood glucose levels were
measured and glucose, insulin, and pyruvate tolerance tests were performed. To explore
the molecular mechanism by which ANGPTL8 regulates hepatic glucose metabolism and
manipulate mouse ANGPTL8 expression levels both in vivo and in vitro based on adenoviral
transduction, gain- and loss-of-function strategies were adopted.
Results
Adenovirus-mediated overexpression of ANGPTL8 decreased fasting blood glucose levels
and improved glucose tolerance and insulin sensitivity in db/db and high-fat diet/streptozotocin-induced
diabetic mice. ANGPTL8 knockdown yielded the opposite effects. ANGPTL8 was upregulated
in the cAMP/Dex-induced hepatocyte gluconeogenesis model. Moreover, ANGPTL8 overexpression
in primary hepatocytes and diabetic mouse livers inhibited the expression of gluconeogenesis-related
genes, including PEPCK and G6PC, by activating the AKT signaling pathway and, thereby, reducing glucose production.
Therefore, the results demonstrated that ANGPTL8 improved glucose metabolism via inhibition
of hepatic gluconeogenesis in diabetic mice.
Conclusions
Current findings highlight a critical role of hepatic ANGPTL8 in glucose homeostasis,
suggesting that increased ANGPTL8 expression could be an underlying factor for the
inhibition of hepatic gluconeogenesis, which could be targeted for the prevention
and treatment of type 2 diabetes.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Metabolism - Clinical and ExperimentalAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Trends in incidence of total or type 2 diabetes: systematic review.BMJ. 2019; 366: l5003https://doi.org/10.1136/bmj.l5003
- Next-generation epidemiology: the role of high-resolution molecular phenotyping in diabetes research.Diabetologia. 2020; 63: 2521-2532
- Current trends in epidemiology of cardiovascular disease and cardiovascular risk management in type 2 diabetes.Metab Clin Exp. 2021; 154838https://doi.org/10.1016/j.metabol.2021.154838
- Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management.Brain J Neurol. 2021; 144: 1632-1645https://doi.org/10.1093/brain/awab079
- Regulation of hepatic glucose metabolism in health and disease.Nat Rev Endocrinol. 2017; 13: 572-587https://doi.org/10.1038/nrendo.2017.80
- Effects of insulin on the metabolic control of hepatic gluconeogenesis in vivo.Diabetes. 2009; 58: 2766-2775https://doi.org/10.2337/db09-0328
- The interaction of hepatic lipid and glucose metabolism in liver diseases.J Hepatol. 2012; 56: 952-964
- Insulin regulation of gluconeogenesis.Ann N Y Acad Sci. 2018; 1411: 21-35https://doi.org/10.1111/nyas.13435
- CREB and FoxO1: two transcription factors for the regulation of hepatic gluconeogenesis.BMB Rep. 2013; 46: 567-574
- Epigenomic and transcriptional control of insulin resistance.J Intern Med. 2016; 280: 443-456
- Hormonal regulation of hepatic glucose production in health and disease.Cell Metab. 2011; 14: 9-19https://doi.org/10.1016/j.cmet.2011.06.003
- Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432https://doi.org/10.1038/372425a0
- Regulation of basal expression of hepatic PEPCK and G6Pase by AKT2.Biochem J. 2020; 477: 1021-1031https://doi.org/10.1042/BCJ20190570
- Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue.Diabetes. 2010; 59: 1338-1348https://doi.org/10.2337/db09-1324
- Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism.Am J Physiol Endocrinol Metab. 2012; 303: E334-E351https://doi.org/10.1152/ajpendo.00084.2012
- Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family.Biochem Biophys Res Commun. 2013; 430: 1126-1131https://doi.org/10.1016/j.bbrc.2012.12.025
- Emerging roles of Lipasin as a critical lipid regulator.Biochem Biophys Res Commun. 2013; 432: 401-405https://doi.org/10.1016/j.bbrc.2013.01.129
- New hormone stimulates pancreatic β-cell proliferation.Lancet Diabetes Endocrinol. 2013; : s12https://doi.org/10.1016/S2213-8587(13)70032-9
- ANGPTL8/betatrophin does not control pancreatic beta cell expansion.Cell. 2014; 159: 691-696https://doi.org/10.1016/j.cell.2014.09.027
- Angiopoietin-like protein 8 (ANGPTL8)/betatrophin overexpression does not increase beta cell proliferation in mice.Diabetologia. 2015; 58: 1523-1531https://doi.org/10.1007/s00125-015-3590-z
- ANGPTL8 (betatrophin) role in diabetes and metabolic diseases.Diabetes/Metab Res Rev. 2017; 33https://doi.org/10.1002/dmrr.2919
- ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase.Mol Metab. 2017; 6: 1137-1149https://doi.org/10.1016/j.molmet.2017.06.014
- Regulation of lipid metabolism by angiopoietin-like proteins.Curr Opin Lipidol. 2016; 27: 249-256https://doi.org/10.1097/MOL.0000000000000290
- Angiopoietin-like 3 in lipoprotein metabolism.Nat Rev Endocrinol. 2017; 13: 731-739https://doi.org/10.1038/nrendo.2017.119
- Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents.Diabetologia. 2018; 61: 1435-1446https://doi.org/10.1007/s00125-018-4579-1
- Regulation of ANGPTL8 in liver and adipose tissue by nutritional and hormonal signals and its effect on glucose homeostasis in mice.Am J Physiol Endocrinol Metab. 2020; 318: E613-E624https://doi.org/10.1152/ajpendo.00339.2019
- In vivo targeted delivery of ANGPTL8 gene for beta cell regeneration in rats.Diabetologia. 2015; 58: 1036-1044https://doi.org/10.1007/s00125-015-3521-z
- Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice.Proc Natl Acad Sci U S A. 2018; 115: E1249-E1258https://doi.org/10.1073/pnas.1717420115
- Circulating betatrophin levels are increased in patients with type 2 diabetes and associated with insulin resistance.J Clin Endocrinol Metab. 2015; 100: E96-100https://doi.org/10.1210/jc.2014-2300
- Increased circulating levels of betatrophin in newly diagnosed type 2 diabetic patients.Diabetes Care. 2014; 37: 2718-2722https://doi.org/10.2337/dc14-0602
- Regulation of angiopoietin-like protein 8 expression under different nutritional and metabolic status.Endocr J. 2019; 66: 1039-1046https://doi.org/10.1507/endocrj.EJ19-0263
- The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking.Open Biol. 2016; 6: 150272https://doi.org/10.1098/rsob.150272
- Mebhydrolin ameliorates glucose homeostasis in type 2 diabetic mice by functioning as a selective FXR antagonist.Metab Clin Exp. 2021; 119: 154771https://doi.org/10.1016/j.metabol.2021.154771
- Dexamethasone-induced Krüppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia.J Clin Invest. 2019; 129: 2266-2278https://doi.org/10.1172/JCI66062
- Adenoviruses as vaccine vectors.Mol Ther: J Am Soc Gene Ther. 2004; 10: 616-629https://doi.org/10.1016/j.ymthe.2004.07.013
- PPP1R3C mediates metformin-inhibited hepatic gluconeogenesis.Metab Clin Exp. 2019; 98: 62-65https://doi.org/10.1016/j.metabol.2019.06.002
- Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids.J Lipid Res. 2020; 61: 1203-1220https://doi.org/10.1194/jlr.RA120000781
- Angiopoietin-like protein 3, a hepatic secretory factor, activates lipolysis in adipocytes.Biochem Biophys Res Commun. 2003; 301: 604-609https://doi.org/10.1016/s0006-291x(02)03058-9
- Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice.Proc Natl Acad Sci U S A. 2005; 102: 6086-6091https://doi.org/10.1073/pnas.0408452102
- ANGPTL8 negatively regulates NF-κB activation by facilitating selective autophagic degradation of IKKγ.Nat Commun. 2017; 8: 2164https://doi.org/10.1038/s41467-017-02355-w
- Angiopoietin-like 8 improves insulin resistance and attenuates adipose tissue inflammation in diet-induced obese mice.Exp Clin Endocrinol Diabetes. 2020; 128: 290-296https://doi.org/10.1055/a-0725-7897
- ANGPTL8 regulates adipocytes differentiation and adipogenesis in bovine.Gene. 2019; 707: 93-99https://doi.org/10.1016/j.gene.2019.04.048
- Angptl8 mediates food-driven resetting of hepatic circadian clock in mice.Nat Commun. 2019; 10: 3518https://doi.org/10.1038/s41467-019-11513-1
- Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis.Proc Natl Acad Sci U S A. 2013; 110: 16109-16114https://doi.org/10.1073/pnas.1315292110
- Insulin upregulates betatrophin expression via PI3K/Akt pathway.Sci Rep. 2017; 7: 5594https://doi.org/10.1038/s41598-017-06052-y
- GLP-1 receptor agonists stimulate ANGPTL8 production through the PI3K/Akt pathway in a GLP-1 receptor-dependent manner.Peptides. 2018; 106: 83-90https://doi.org/10.1016/j.peptides.2018.07.001
- Circulating betatrophin is increased in patients with overt and subclinical hypothyroidism.Biomed Res Int. 2016; 2016: 5090852https://doi.org/10.1155/2016/5090852
- Angiopoietin-like protein 8 is a novel vitamin D receptor target gene involved in nonalcoholic fatty liver pathogenesis.Am J Pathol. 2018; 188: 2800-2810https://doi.org/10.1016/j.ajpath.2018.07.028
- Interaction between glucose and lipid metabolism: more than diabetic dyslipidemia.Diabetes Metab J. 2015; 39: 353-362
- ANGPTL8 enhances insulin sensitivity by directly activating insulin-mediated AKT phosphorylation.Gene. 2020; 749: 144707https://doi.org/10.1016/j.gene.2020.144707
- ANGPTL8/betatrophin alleviates insulin resistance via the Akt-GSK3β or Akt-FoxO1 pathway in HepG2 cells.Exp Cell Res. 2016; 345: 158-167https://doi.org/10.1016/j.yexcr.2015.09.012
- Metabolites as regulators of insulin sensitivity and metabolism.Nat Rev Mol Cell Biol. 2018; 19: 654-672https://doi.org/10.1038/s41580-018-0044-8
- Angptl8CRISPR/Cas9-mediated knockout suppresses plasma triglyceride concentrations and adiposity in rats.J Lipid Res. 2018; 59: 1575-1585https://doi.org/10.1194/jlr.M082099
- Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement.Diabetes. 2003; 52: 2905-2913https://doi.org/10.2337/diabetes.52.12.2905
- Insulin-associated weight gain in obese type 2 diabetes mellitus patients: what can be done?.Diabetes Obes Metab. 2017; 19: 1655-1668https://doi.org/10.1111/dom.13009
- Host factors alter effects of angiopoietin-like protein 8 on glucose homeostasis in diabetic mice.J Diabetes Mellitus. 2016; 6: 277-290https://doi.org/10.4236/jdm.2016.64029
Article info
Publication history
Published online: October 26, 2021
Accepted:
October 21,
2021
Received:
July 2,
2021
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
