Metabolism - Clinical and Experimental - Articles in Press

The sympathetic nervous system regulates the three glycerol-3P generation pathways in white adipose tissue of fasted, diabetic and high-protein diet-fed rats - Corrected Proof

2012-05-17

Abstract: The aim of the present study was to investigate the participation of the sympathetic nervous system (SNS) in the control of glycerol-3-P (G3P) generating pathways in white adipose tissue (WAT) of rats in three situations in which the plasma insulin levels are low. WAT from 48h fasted animals, 3day-streptozotocin diabetic animals and high-protein, carbohydrate-free (HP) diet-fed rats was surgical denervated and the G3P generation pathways were evaluated. Food deprivation, diabetes and the HP diet provoke a marked decrease in the rate of glucose uptake and glycerokinase (GyK) activity, but a significant increase in the glyceroneogenesis, estimated by the phosphoenolpyruvate carboxykinase (PEPCK) activity and the incorporation of 1-[14C]-pyruvate into glycerol–TAG. The denervation provokes a reduction (~70%) in the NE content of WAT in fasted, diabetic and HP diet-fed rats. The denervation induced an increase in WAT glucose uptake of fed, fasted, diabetic and HP diet-fed rats (40%, 60%, 3.2 fold and 35%, respectively). TAG–glycerol synthesis from pyruvate was reduced by denervation in adipocytes of fed (58%) and fasted (36%), saline-treated (58%) and diabetic (23%), and HP diet-fed rats (11%). In these same groups the denervation reduced the PEPCK mRNA expression (75%–95%) and the PEPCK activity (35%–60%). The denervation caused a ~35% decrease in GyK activity of control rats and a further ~35% reduction in the already low enzyme activity of fasted, diabetic and HP diet-fed rats. These data suggest that the SNS plays an important role in modulating G3P generating pathways in WAT, in situations where insulin levels are low.

Leptin in congenital or HIV-associated lipodystrophy and metabolic syndrome: A need for more mechanistic studies and large, randomized, placebo-controlled trials - Corrected Proof

Joo-Pin Foo, Christos S. Mantzoros — 2012-05-17

Lipodystrophy is a clinically heterogeneous group of disorders characterized by abnormal adipose tissue metabolism, which is almost always complicated by metabolic derangements. The abnormal adipose tissue metabolism, a hallmark of this condition, manifests as either loss of subcutaneous adipose tissue (lipoatrophy) or fat accumulation (lipohypertrophy) at different body areas, and the condition is invariably associated with varying degrees of insulin resistance and dyslipidemia. Lipodystrophy can be congenital or acquired, though the congenital forms are rarely seen. The commonest form of acquired lipodystrophy in the current world is those associated with human immunodeficiency virus (HIV) infection, with approximately more than 100,000 such patients in the United States . The exact incidence of the condition is difficult to estimate due to the lack of universally accepted diagnostic criteria. The incidence is especially made more pronounced by the increasing incidence of HIV infection and the associated use of Highly Active Antiretroviral Therapy (HAART). With the advent of better treatment options for HIV positive individuals, which have dramatically improved the survival of HIV subjects , the prevalence of HIV the associated lipodystrophy will undoubtedly become more significant in the coming years.

Sulfated oxysterol 25HC3S as a therapeutic target of non-alcoholic fatty liver disease - Corrected Proof

Ji-Young Cha, Young-Bum Kim — 2012-05-16

In mammals, triglycerides are predominantly synthesized in the liver by de novo lipogenesis and in turn, exported in the form of very low density lipoprotein (VLDL) particles to adipose and other tissues . Although triglycerides serve as an important source of energy during fasting, excessive accumulation of triglycerides in the liver resulted in hepatic steatosis (fatty liver), a major element of liver diseases such as non-alcoholic fatty liver disease (NAFLD) . NAFLD affects one-third of the adult population and is found in more than two thirds of obese people in the United States . It is clear that NAFLD is strongly associated with obesity and insulin resistance but its pathogenesis is not fully understood and therapeutic options are limited . Hepatic steatosis is often developed when fatty-acid metabolism is unbalanced in several ways, including uncontrolled delivery of free fatty acids to the liver from adipose tissue and inadequate de novo synthesis of triglycerides . Lipogenesis is thought to be regulated via the transcription factors sterol regulatory element binding protein-1c (SREBP-1c) and carbohydrate response element binding protein (ChREBP), both of which are increased by insulin and glucose . Evidence also suggests that the sterol and glucose sensor, liver X receptors (LXRs) play important roles in regulating the lipogenic pathway .

Effects of an intensive behavioral weight loss intervention consisting of caloric restriction with or without physical activity on common carotid artery remodeling in severely obese adults - Corrected Proof

2012-05-11

Abstract: Objective: Obesity increases cardiovascular disease risk and adversely affects vascular structure and function. Few studies have evaluated the vascular effects of non-surgical weight reduction in the severely obese. We hypothesized that weight loss and improvements in cardiometabolic factors would reduce common carotid artery intima-media thickness (CIMT) and inter-adventitial diameter (AD) in severely obese adults.Methods: We performed carotid ultrasound and measured cardiometabolic factors in 90 severely obese participants (body mass index (BMI)≥35kg/m2, age 30–55) at baseline and 6months in a randomized clinical trial of dietary intervention with (n=45) or without (n=45) physical activity.Results: The achieved weight loss (mean=8%) did not differ significantly by intervention group (P=0.10) and resulted in a 0.07mm mean decrease in AD (P=0.001). AD change was positively correlated with changes in BMI, waist circumference, abdominal visceral and subcutaneous fat, and body fat mass, and AD decreased more in men (P<0.05 for all). After multivariable adjustment, changes in BMI (P=0.03) and abdominal subcutaneous fat (P=0.04) were significant determinants of AD change. Although CIMT did not decrease significantly overall (-0.008mm, P=0.16), individuals who lost at least 5% of their body weight experienced a significant mean reduction in CIMT of 0.02mm (P=0.002). CIMT change was positively correlated with changes in BMI, waist circumference, fat-free mass, leptin, and insulin (P<0.05 for all). After multivariable adjustment, insulin reduction remained a significant determinant of CIMT decrease (P=0.03).Conclusion: A 6 month intensive behavioral intervention can significantly reverse metabolic and vascular abnormalities in severely obese adults.

Caffeic acid phenethyl ester reduces the activation of the nuclear factor κB pathway by high-fat diet-induced obesity in mice - Corrected Proof

2012-05-10

Abstract: Objective: The aim of this study was to investigate the effect of CAPE on the insulin signaling and inflammatory pathway in the liver of mice with high fat diet induced obesity.Material/Methods: Swiss mice were fed with standard chow or high-fat diet for 12-week. After the eighth week, animals in the HFD group with serum glucose levels higher than 200mg/dL were divided into two groups, HFD and HFD receiving 30mg/kg of CAPE for 4weeks. After 12weeks, the blood samples could be collected and liver tissue extracted for hormonal and biochemical measurements, and insulin signaling and inflammatory pathway analyzes.Results: The high-fat diet group exhibited more weight gain, glucose intolerance, and hepatic steatosis compared with standard diet group. The CAPE treatment showed improvement in glucose sensitivity characterized by an area under glucose curve similar to the control group in an oral glucose tolerance test Furthermore, CAPE treatment promoted amelioration in hepatic steatosis compared with the high-fat diet group. The increase in glucose sensitivity was associated with the improvement in insulin-stimulated phosphorylation of the insulin receptor substrate-2, followed by an increase in Akt phosphorylation. In addition, it was observed that CAPE reduced the induction of the inflammatory pathway, c-jun-N- terminal kinase, the nuclear factor kappa B, and cyclooxygenase-2 expression, respectively.Conclusions: Overall, these findings indicate that CAPE exhibited anti-inflammatory activity that partly restores normal metabolism, reduces the molecular changes observed in obesity and insulin resistance, and therefore has a potential as a therapeutic agent in obesity.

Ginsenoside Re rapidly reverses insulin resistance in muscles of high-fat diet fed rats - Corrected Proof

2012-05-09

Abstract: Objective: In a previous study, it was found that a ginseng berry extract with a high content of the ginsenoside Re normalized blood glucose in ob/ob mice. The objective of this study was to evaluate the effect of the ginsenoside Re on insulin resistance of glucose transport in muscles of rats made insulin resistant with a high-fat diet.Material/method: Rats were fed either rat chow or a high-fat diet for 5 weeks. The rats were then euthanized, and insulin stimulated glucose transport activity was measured in epitrochlearis and soleus muscle strips in vitro.Results: Treatment of muscles with Re alone had no effect on glucose transport. The high-fat diet resulted in ~50% decreases in insulin responsiveness of GLUT4 translocation to the cell surface and glucose transport in epitrochlearis and soleus muscles. Treatment of muscles with Re in vitro for 90 min completely reversed the high-fat diet-induced insulin resistance of glucose transport and GLUT4 translocation. This effect of Re is specific for insulin stimulated glucose transport, as Re treatment did not reverse the high-fat diet-induced resistance of skeletal muscle glucose transport to stimulation by contractions or hypoxia.Conclusions: Our results show that the ginsenoside Re induces a remarkably rapid reversal of high-fat diet-induced insulin resistance of muscle glucose transport by reversing the impairment of insulin-stimulated GLUT4 translocation to the cell surface.

Adipocytokine profiles in a putative novel postmenopausal polycystic ovary syndrome (PCOS) phenotype parallel those in premenopausal PCOS: the Rancho Bernardo Study - Corrected Proof

Andrew J. Krentz, Denise von Mühlen, Elizabeth Barrett-Connor — 2012-05-07

Abstract: The objective was to investigate whether the associations between leptin, adiponectin, andadiposity reported in classic polycystic ovary syndrome (PCOS) are also observed in elderly women with a novel putative postmenopausal PCOS phenotype. We studied 713 postmenopausal community-dwelling women. Diagnosis of the novel phenotype required the presence of ≥3 diagnostic features including: 1) a personal history of oligomenorrhea; 2) history of infertility or miscarriage; 3) current or past clinical or hormonal evidence of hyperandrogenism; 4) central obesity; 5) biochemical evidence of insulin resistance. Women in the control group had ≤2 of these components. Mean age (±SD) was 74±8 years for the study cohort. Sixty-six women (9.3%) had the putative PCOS phenotype. Serum leptin was higher (mean 25.70±15.67 vs 14.94+9.89 ng/mL, P<.01) and adiponectin lower (mean 11.72±4.80 vs 17.31±7.45 μg/mL, P<.01) in cases vs controls. Leptin was positively, and adiponectin inversely, associated with an increasing number of phenotype features (P<.01 for linearity). In age-adjusted regression analysis, adjustment for waist circumference eliminated the association between leptin and the PCOS phenotype, but not the association between adiponectin and the PCOS phenotype. In this novel postmenopausal PCOS phenotype, adipocytokine profiles and their associations with adiposity parallel those reported in younger women with classic PCOS. These results support our hypothesis that a putative phenotype analogous to PCOS can be identified in postmenopausal women using clinical and biochemical criteria. Use of this novel phenotype could provide a basis for studies of the delayed consequences of PCOS in older women.

Downregulation of GPR83 in the hypothalamic preoptic area reduces core body temperature and elevates circulating levels of adiponectin - Corrected Proof

2012-05-07

Abstract: The G protein-coupled receptor 83 (GPR83) was recently demonstrated in warm sensitive neurons (WSN) of the hypothalamic preoptic area (POA) that participate in temperature homeostasis. Thus, we investigated whether GPR83 may have a role in regulating core body temperature (CBT) by reducing its expression in the POA. Dissipation of energy in the form of heat is the primary mode of energy expenditure in mammals and can ultimately affect energy homeostasis. Thus, we also measured the level of important regulators of metabolism. Downregulation of GPR83 was obtained by lentiviral short-hairpin RNAs (shGPR83) vectors designed and selected for their ability to reduce GPR83 levels in vitro. Mice received POA injection of shGPR83 or non-silencing vectors and were monitored for CBT, motor activity, food intake body weight and circulating levels of IGF-1, insulin, leptin and adiponectin. Down-regulation of GPR83 in the POA resulted in a small (0.15°C) but significant reduction of CBT during the dark/active cycle of the day. Temperature reduction was followed by increased body weight gain independent of caloric intake. shGPR83 mice also had increased level of circulating adiponectin (31916±952pg/mL vs. 23474±1507pg/mL, P<.01) while no change was observed for insulin, IGF-1 or leptin. GPR83 may participate in central thermoregulation and the central control of circulating adiponectin. Further work is required to determine how GPR83 can affect POA WSN and what are the long term metabolic consequences of its down-regulation.

Oral β-blockade in relation to energy expenditure in clinically stable patients with liver cirrhosis: A double-blind randomized cross-over trial - Corrected Proof

Wai Gin Lee, John L. McCall, Edward J. Gane, Rinki Murphy, Lindsay D. Plank — 2012-05-07

Abstract: Elevated resting energy expenditure (REE) is seen in liver cirrhosis and is associated with reduced transplant-free survival. Non-selective β-blockers reduce REE in acute hypermetabolic conditions. We examined whether non-selective β-blockers reduce REE in patients with stable liver cirrhosis. Twenty-two stable cirrhotic patients (Child–Pugh grading: 19A, 2B, 1C) were randomized to 3-month treatment with nadolol (titrated to decrease resting pulse rate by 20%) or placebo and after a 1-month washout period crossed to the alternative treatment for a further 3months. REE was measured by indirect calorimetry and total body protein by neutron activation analysis at the beginning and end of each 3-month period of treatment. A predicted REE was calculated for each patient based on total body protein. A measured to predicted REE ratio >1.22 indicated significantly elevated REE. The primary outcome was REE at the end of 3-month treatment with nadolol compared with placebo. Elevated REE was seen in one patient at study entry. After 3months on placebo REE was 1506±40 (SEM) kcal/d and on nadolol, 1476±40kcal/d, a mean reduction of 31±16kcal/d (P=.076). Total body protein changes were not significant. Nadolol was well tolerated with no increase in the rate of adverse events. In stable cirrhotic patients, nadolol was not associated with reduction in REE. A larger, longer-term study with different eligibility criteria is required to investigate whether this treatment offers benefits additional to its use for prevention of variceal hemorrhage.

Insulin and contraction-induced movement of fatty acid transport proteins to skeletal muscle transverse-tubules is distinctly different than to the sarcolemma - Corrected Proof

Leslie E. Stefanyk, Arend Bonen, David J. Dyck — 2012-05-07

Abstract: Fatty acid (FA) transport proteins are known to exist on the sarcolemma of skeletal muscle. However, it is unknown whether the t-tubules, which comprise ~60% of the cell surface, also harbor these proteins. We examined FA transport proteins from both membrane fractions in unstimulated, insulin-stimulated and contracted skeletal muscle. Sarcolemmal and t-tubule membrane fractions were isolated from the same muscle homogenate using a discontinuous sucrose gradient. Our results demonstrate that the relative content of FA transport proteins within the two fractions and the magnitude to which they increase when stimulated were distinctly different. In unstimulated muscle FAT/CD36, FATP4, and FABPpm are abundant on the sarcolemma (3-, 8-, and 10-fold greater than t-tubule, respectively), whereas FATP1 resides primarily within the t-tubule fraction (1- to 2-fold greater than the sarcolemma). With both stimuli, in terms of absolute increase, FAT/CD36 predominantly translocated to the sarcolemma and FATP1 to the t-tubules. There are clear differences in the profile of FA transport proteins and the response to stimuli of the sarcolemma and t-tubules. FATP1, a variable and unresponsive protein on the sarcolemma, appears to reside primarily in the t-tubules where it is responsive to stimuli.

Self-reported speed of eating and 7-year risk of type 2 diabetes mellitus in middle-aged Japanese men - Corrected Proof

2012-05-07

Abstract: Objective: This cohort study investigated the association between eating speed and the incidence of type 2 diabetes in middle-aged Japanese men.Materials/Methods: Participants were 2,050 male employees of a metal products factory in Japan. We measured self-reported categorical eating speed. The incidence of diabetes was determined in annual medical examinations over a 7-year period. The association between eating speed and the incidence of diabetes adjusted for multiple variables (age, family history of diabetes, smoking, alcohol drinking, habitual exercise, and presence of hypertension and hyperlipidemia) was evaluated using Cox proportional hazards models.Results: The prevalence of obesity (BMI≥25kg/m2) across the categories of eating speed (slow, medium, and fast) was 14.6, 23.3, and 34.8%, respectively, and a faster eating speed was associated with a higher prevalence of obesity. During the study, 177 participants developed diabetes. Crude incidence rates (/1,000 person-years) across the three categories of eating speed were 9.9, 15.6, and 17.3, respectively. Multivariate-adjusted hazard ratios (95% CI) across the categories were 1.00 (reference), 1.68 (0.93-3.02), and 1.97 (1.10-3.55), respectively, and eating speed was associated with the risk of diabetes (p for trend=0.030). After further adjustment for BMI, a significant association was not observed.Conclusions: Eating speed was associated with the incidence of diabetes. Since these associations were not significant after adjusting for BMI, eating speed may act via its effect on body weight. Eating speed is a controllable risk factor, and eating slowly could be an acceptable lifestyle intervention for the prevention of diabetes mellitus.

Abnormal expression and function of Dectin-1 receptor in type 2 diabetes mellitus patients with poor glycemic control (HbA1c>8%) - Corrected Proof

2012-05-04

Abstract: Dectin-1 is a key innate receptor involved in various cellular responses and may have a direct role in chronic inflammatory conditions such as type 2 diabetes mellitus. The aim of this work was to evaluate the expression and function of Dectin-1 in peripheral blood mononuclear cells from T2D patients. Dectin-1 expression was analyzed by flow cytometry and RT-PCR in monocytes and lymphocyte subpopulations from T2D patients (n=34) and healthy subjects (n=29). Functional assays were used to assess cytokine synthesis, ROS levels and oxidative stress ratio. We found increased expression (MFI) of Dectin-1 in monocytes from T2D patients. Significantly higher Dectin-1 expression was also detected in CD4+ T, CD8+ T, B cells and NK cells from T2D patients compared to controls. In contrast, monocytes from T2D patients with poor glycemic control (HbA1c>8%) showed a diminished percentage of Dectin-1+/TLR2+ cells. Negative correlations between the percent of Dectin-1+/TLR2+ cells and fasting plasma glucose levels (FPG) and HbA1c levels were found. A significant reduction in basal levels of IL-10 was observed in patients with poor glycemic control (HbA1c>8%) compared to patients with appropriate glycemic control (HbA1c≤6.5%) and healthy controls, an effect that was not observed in monocytes stimulated with zymosan. Higher ROS levels in zymosan-stimulated cells from patients with poor glycemic control positively correlated with FPG levels, and the oxidative stress ratio was higher in T2D cells compared with controls. Our data indicate that Dectin-1 may be involved in the abnormal immune responses that are observed in patients with T2D.

GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases - Corrected Proof

2012-05-03

Abstract: Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular and renal diseases but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits oxidative stress and albuminuria in streptozotocin (STZ)-induced type 1 diabetes mellitus rats, via a protein kinase A (PKA)-mediated inhibition of renal NAD(P)H oxidases. Diabetic rats were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Oxidative stress markers (urinary 8-hydroxy-2′-deoxyguanosine and renal dihydroethidium staining), expression of renal NAD(P)H oxidase components, transforming growth factor-β (TGF-β), fibronectin and urinary albumin excretion were measured. In vitro effect of liraglutide was evaluated using cultured renal mesangial cells. Administration of liraglutide did not affect plasma glucose levels or body weights in STZ diabetic rats, but normalized oxidative stress markers, expression of NAD(P)H oxidase components, TGF-β, fibronectin in renal tissues and urinary albumin excretion, all of which were significantly increased in diabetic rats. In addition, in cultured renal mesangial cells, incubation with liraglutide for 48 h inhibited NAD(P)H-dependent superoxide production evaluated by lucigenin chemiluminescence in a dose-dependent manner. This effect was reversed by both PKA inhibitor H89 and adenylate cyclase inhibitor SQ22536, but not by Epac2 inhibition via its small interfering RNA. Liraglutide may have a direct beneficial effect on oxidative stress and diabetic nephropathy via a PKA-mediated inhibition of renal NAD(P)H oxidase, independently of a glucose-lowering effect.

Altered baroreflex and autonomic modulation in monosodium glutamate-induced hyperadipose rats - Corrected Proof

2012-05-03

Abstract: We aimed to examine the cardiovascular function by tonic and baroreflex alterations in obese rats induced by monosodium glutamate (MSG). Neonatal male Wistar rats were injected with MSG (4 mg/g body weight) or equimolar saline (control, C). At 90 days, all rats were anesthetized for catheterization of the femoral artery for mean arterial pressure (MAP) and heart rate (HR) recordings in the conscious state. After baseline, we performed IV treatment with hexamethonium (25 mg/kg), or atropine (1 mg/kg) or propranolol (3 mg/kg). We also performed the spectral analysis of heart rate variability (HRV) and baroreflex sensitivity. Baseline comparison showed that obese rats are hypertensive compared with control (C=110±2 mmHg; MSG=: 123±3 mmHg, P<0.05). After ganglionic blockade with hexamethonium the differences in MAP between control and obese rats disappeared. Beta adrenergic blockade with propranolol induced a greater decrease in heart rate compared with control. The analysis of HRV showed that obese rats have increased modulation by both components of the autonomic nervous system compared with control rats. The baroreflex gain showed increased sensitivity for the parasympathetic component in the obese rats (C=−2.41±0.25; MSG=−3.34±0.23 bpm/mmHg) compared with control. Our data suggest that both components of autonomic cardiac tonus and the parasympathetic component of the baroreflex sensitivity are increased in the MSG obese rat. It is possible that the parasympathetic alterations observed in these MSG obese rats may have originated from central areas of cardiovascular control.

VEGF and angiopoietins in diabetic glomerulopathy: How far for a new treatment? - Corrected Proof

Alessandra Dei Cas, Luigi Gnudi — 2012-05-03

Abstract: Diabetic nephropathy (DN) is the major cause of end-stage renal disease in Western countries and its prevalence continues to increase (United States Renal Data System 2010, http://www.usrds.org/). Treatments currently utilised for DN provide only partial renoprotection, hence the need to identify new targets for therapeutic intervention. Metabolic and haemodynamic abnormalities have been implicated in the pathogenesis of DN, triggering the activation of intracellular signaling molecules that lead to the dysregulation of vascular growth factors and cytokines, such as vascular endothelial growth factor (VEGF) and angiopoietins, important players in the functional and structural regulation of the glomerular filtration barrier. This review focuses on the importance of VEGF-A and angiopoietins in kidney physiology and in the diabetic kidney, exploring their potential therapeutic role in the prevention and delay of diabetic glomerulopathy.

Adipose triglyceride lipase and hormone-sensitive lipase protein expression in subcutaneous adipose tissue is decreased after an isoenergetic low-fat high-complex carbohydrate diet in the metabolic syndrome - Corrected Proof

2012-05-02

Abstract: The objective was to determine the contribution of dietary fat quantity and composition to lipolysis and lipolytic gene expression in humans in relation to obesity, insulin resistance, and the metabolic syndrome (MetS). Men and women with the MetS were randomly assigned to one of four isoenergetic diets: a high-fat saturated fat diet (n=10), a high-fat monounsaturated fat diet (n=7), and two low-fat high-complex carbohydrate (LFHCC) diets, one supplemented with 1.24g/day long-chain n-3 PUFA (LFHCC: n=7, LFHCCn-3: n=8). Subcutaneous adipose tissue biopsies were taken before and after the 12-week dietary intervention period. ATGL and HSL mRNA and protein expression was determined. Whole body rate of appearance of free fatty acids (RaFFA) was determined by intravenous infusion of [2H2]-palmitate in a subgroup of men (n=20). Adipose tissue ATGL and HSL mRNA and protein expression was not affected by alterations in dietary fat composition. Pooled analysis comparing the low- and high-fat diets showed that ATGL and HSL protein expression was significantly reduced after the LFHCC diets (P=.04), irrespective of long-chain n-3 PUFA. Moreover, LFHCC diets lowered fasting insulin, HOMAIR, and (LDL)-cholesterol concentrations (P≤.05). Changes in ATGL and HSL protein expression was positively associated with changes in whole body RaFFA (P<.03). The low-fat high-complex carbohydrate diets reduced ATGL and HSL protein expression and significantly improved circulating lipids and insulin sensitivity. Under isoenergetic conditions, dietary fat quantity, rather than composition, may be most important for modulating subcutaneous adipose tissue ATGL and HSL protein expression.

Allelic variations in the vitamin D receptor gene, insulin secretion and parents' heights are independently associated with height in obese children and adolescents - Corrected Proof

2012-05-02

Abstract: Polymorphisms in the VDR gene were reported to be associated with variations in intrauterine and postnatal growth and with adult height, but also with other traits that are strongly correlated such as the BMI, insulin sensitivity, insulin secretion and hyperglycemia. Here, we assessed the impact of VDR polymorphisms on body height and its interactions with obesity- and glucose tolerance-related traits in obese children and adolescents. We studied 173 prepubertal (Tanner's stage 1) and 146 pubertal (Tanner's stages 2–5) obese children who were referred for a weight-loss program. Three single nucleotide polymorphisms were genotyped: rs1544410 (BsmI), rs7975232 (ApaI) and rs731236 (TaqI). BsmI and TaqI genotypes were significantly associated with height in pubertal children, but the associations did not reach statistical significance in prepubertal children. In stepwise regression analyses, the lean body mass, insulin secretion, BsmI or TaqI genotypes and the father's and the mother's height were independently and positively associated with height in pubertal children. These covariables accounted for 46% of the trait variance. The height of homozygous carriers of the minor allele of BsmI was 0.65 z-scores (4cm) higher than the height of homozygous carriers of the major allele (P=.0006). Haplotype analyses confirmed the associations of the minor alleles of BsmI and TaqI with increased height. In conclusion, VDR genotypes were significantly associated with height in pubertal obese children. The associations were independent from the effects of confounding traits, such as the body fat mass, insulin secretion, insulin sensitivity and glucose tolerance.

Leptin replacement therapy does not improve the abnormal lipid kinetics of hypoleptinemic patients with HIV-associated lipodystrophy syndrome - Corrected Proof

2012-04-30

Abstract: Patients with HIV-associated dyslipidemic lipodystrophy (HADL) have characteristic lipid kinetic defects: accelerated lipolysis, blunted fat oxidation and increased hepatic fatty acid reesterification. HADL patients with lipoatrophy also have leptin deficiency. Small or non-randomized studies have suggested that leptin replacement improves glucose metabolism in HADL, with very limited data regarding its effects on the lipid kinetic abnormalities. We performed a randomized, double-blind, placebo-controlled, dose-escalating (0.02mg/kg/d for two months; 0.04mg/kg/d for a further two months) study of the effects of metreleptin on lipid kinetics in 17 adults with HADL, hypertriglyceridemia and hypoleptinemia. Rates of lipolysis, intra-adipocyte and intrahepatic reesterification and fatty acid oxidation were measured using infusions of 13C1-palmitate and 2H5-glycerol, and indirect calorimetry. Fasting lipid profiles and glucose and insulin responses to oral glucose challenge were also measured. Metreleptin treatment induced significant, dose-dependent increases in fasting plasma leptin levels. There was no significant change in total lipolysis, net lipolysis, adipocyte or hepatic re-esterification or fatty acid oxidation, or in fasting triglyceride or HDL-C concentrations, with metreleptin treatment. Metreleptin decreased fasting non-HDL-C levels (P<.01) and area-under-the-curve for glucose (P<.05). In hypoleptinemic HADL patients, treatment with metreleptin at 0.02 or 0.04mg/kg/d does not improve abnormal fasting lipid kinetics, or triglyceride or HDL-C levels. Metreleptin does, however, improve glycemia and non-HDL-C in these patients. These results suggest a dissociation between leptin's effects on glucose metabolism compared to those on lipid kinetics in HADL.

Krill powder increases liver lipid catabolism and reduces glucose mobilization in tumor necrosis factor-alpha transgenic mice fed a high-fat diet - Corrected Proof

2012-04-27

Abstract: A promising approach to ameliorate obesity and obesity-associated diseases is the identification of new sources of dietary ingredients. The present study investigated the hepatic regulation of energy metabolism after feeding a powder isolated from Antarctic krill (Euphausia superba) in a transgenic mouse model of chronic inflammation (human tumor necrosis factor-alpha (hTNFα) mice) known to display unfavorable effects on lipid metabolism. Male hTNFα mice were fed high-fat diets (23.6%, w/w) with or without krill powder (6.4% lipids, 4.3% protein, w/w) for 6weeks. Blood, liver lipid, and fatty acid composition, as well as hepatic enzyme activities and gene expressions, were determined. Krill powder fed mice displayed lowered hepatic and plasma triacylglycerol levels compared to mice on a high-fat casein diet. This was accompanied by down-regulated hepatic expression of genes involved in lipogenesis and glycerolipid synthesis, and increased β-oxidation activity. In addition, the krill powder diet lowered plasma levels of cholesterol, as well as hepatic gene expression of sterol regulatory element binding transcription factor 2 (SREBP2) and enzymes involved in cholesterol synthesis. Notably, genes involved in glycolysis and gluconeogenesis were significantly reduced in liver by the krill powder diet, while genes involved in oxidative phosphorylation and uncoupling were not affected. Krill powder also reduced endogenous TNFα in liver, indicating an anti-inflammatory effect. In a high-fat mouse model with disturbed lipid metabolism due to persistent hTNFα expression, krill powder showed significant effects on hepatic glucose- and lipid metabolism, resulting in an improved lipid status in liver and plasma.

Ginger consumption enhances the thermic effect of food and promotes feelings of satiety without affecting metabolic and hormonal parameters in overweight men: A pilot study - Corrected Proof

2012-04-26

Abstract: Evidence suggests that ginger consumption has anti-inflammatory, anti-hypertensive, glucose-sensitizing, and stimulatory effects on the gastrointestinal tract. This study assessed the effects of a hot ginger beverage on energy expenditure, feelings of appetite and satiety and metabolic risk factors in overweight men. Ten men, age 39.1±3.3 y and body mass index (BMI) 27.2±0.3kg/m2, participated in this randomized crossover study. Resting state energy expenditure was measured using indirect calorimetry and for 6h after consumption of a breakfast meal with or without 2g ginger powder dissolved in a hot water beverage. Subjective feelings of satiety were assessed hourly using visual analog scales (VAS) and blood samples were taken fasted and for 3h after breakfast consumption. There was no significant effect of ginger on total resting energy expenditure (P=.43) or respiratory quotient (P=.41). There was a significant effect of ginger on thermic effect of food (ginger vs control=42.7±21.4kcal/d, P=.049) but the area under the curve was not different (P=.43). VAS ratings showed lower hunger (P=.002), lower prospective food intake (P=.004) and greater fullness (P=.064) with ginger consumption versus control. There were no effects of ginger on glucose, insulin, lipids, or inflammatory markers. The results, showing enhanced thermogenesis and reduced feelings of hunger with ginger consumption, suggest a potential role of ginger in weight management. Additional studies are necessary to confirm these findings.

Beneficial effect of branched-chain amino acid supplementation on glycemic control in chronic hepatitis C patients with insulin resistance: Implications for type 2 diabetes - Corrected Proof

2012-04-23

Abstract: Branched-chain amino acids (BCAAs) improve disorders of albumin metabolism, quality of life, subjective symptoms, and prognosis in patients with chronic hepatitis. However, it remains unclear whether they improve insulin resistance. We examined the effects of BCAAs on glucose tolerance and insulin sensitivity in patients with chronic hepatitis C and insulin resistance. Individuals with a definitive diagnosis of chronic hepatitis C and insulin resistance were eligible for participation. Eligible participants were randomly assigned to the BCAA group or a control group. Participants were then crossed over to the other treatment for a further 12weeks. Baseline clinical features, laboratory markers, fatty acid levels, and insulin sensitivity, assessed with oral glucose tolerance tests and a hyperinsulinemic euglycemic clamp, were also examined before and 12 and 24weeks after the beginning of the study. Of the 27 patients who completed the study, 14 began in the BCAA group and 13 began as controls. There were no significant differences in glucose metabolism parameters or lipid profiles between the groups. HbA1c values were improved in 10 patients and worsened or remained unchanged in 17 patients. The only predictive variable for change in HbA1c was the baseline Matsuda index: the lower the index, the greater the improvement in HbA1c values. BCAA therapy did not have adverse effects on glucose tolerance or insulin sensitivity in patients with chronic hepatitis C and insulin resistance. Moreover, it had a therapeutic effect on HbA1c values in patients with marked peripheral (primarily muscle) insulin resistance.

Retinol-binding protein 4, insulin resistance and pregnancy - Corrected Proof

Viroj Wiwanitkit — 2012-04-20

Sir, the recent publication on retinol-binding protein 4 (RBP4), insulin resistance (IR) and pregnancy is very interesting . Khovidhunkit et al concluded, “Serum RBP4 levels in pregnancy are not associated with IR.” . This report is very interesting but is discordant with previous reports. RBP4 is discussed in terms of its clinical correlation to gestational diabetes mellitus (GDM) and other metabolic disorders in pregnancy . Increased RBP4 levels are observed in GDM. Inoue et al also mentioned that circulating RBP4 was elevated in cases of pregnancy-induced hypertension due to altered glucose metabolism . A previous report by Choi et al reported, “Severity of glucose intolerance in women with pGDM is associated with high RBP4 and low adiponectin concentrations.” . A similar report on the significant correlations of RBP4 was also published by Chan et al . The differences in findings among the reports in this area reflect current discrepancies in this issue. There are some points to be considered. First, there are differences in subjects' backgrounds (including both genetic and environmental factors). In addition, the measurement techniques for RBP4 and other parameters differ (analyzer, quality control, etc.). Additionally, there are confounding conditions that lead to fluctuations in RBP4 levels (e.g., uric acid metabolism) . These factors must be considered in assessment studies .

Atorvastatin and pitavastatin enhance lipoprotein lipase production in L6 skeletal muscle cells through activation of adenosine monophosphate-activated protein kinase - Corrected Proof

2012-04-20

Abstract: Pravastatin and atorvastatin increase the serum level of lipoprotein lipase (LPL) mass in vivo but do not increase LPL activity in 3T3-L1 preadipocytes in vitro. LPL is mainly produced by adipose tissue and skeletal muscle cells. Metformin enhances LPL in skeletal muscle through adenosine monophosphate-activated protein kinase (AMPK) activation but not in adipocytes. This study aimed to examine the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on LPL production and to investigate the mechanism by which statins enhance skeletal muscle cell LPL production. L6 skeletal muscle cells were incubated with pravastatin, simvastatin, atorvastatin or pitavastatin. LPL activity, protein levels and mRNA expression were measured. Atorvastatin and pitavastatin significantly increased LPL activity, protein levels and mRNA expression in L6 skeletal muscle cells at 1μmol/L, but neither statin had an effect at 10μmol/L. We measured AMPK to clarify the mechanism by which statins increase LPL production in skeletal muscle cells. At 1μmol/L, both atorvastatin and pitavastatin enhanced AMPK activity, but this enhancement was abolished when AMPK signaling was blocked by compound C. The increased expressions of LPL protein and mRNA by atorvastatin and pitavastatin were reduced by compound C. In addition, mevalonic acid abolished atorvastatin- and pitavastatin-induced AMPK activation and LPL expression. These results suggest that atorvastatin and pitavastatin increase LPL activity, protein levels and LPL mRNA expression by activating AMPK in skeletal muscle cells.

Casein protein results in higher prandial and exercise induced whole body protein anabolism than whey protein in Chronic Obstructive Pulmonary Disease - Corrected Proof

2012-04-18

Abstract: Exercise is known to improve physical functioning and health status in Chronic Obstructive Pulmonary Disease (COPD). Recently, disturbances in protein turnover and amino acid kinetics have been observed after exercise in COPD. The objective was to investigate which dairy protein is able to positively influence the protein metabolic response to exercise in COPD. 8 COPD patients and 8 healthy subjects performed a cycle test on two days while ingesting casein or whey protein. Whole body protein breakdown (WbPB), synthesis (WbPS), splanchnic amino acid extraction (SPE), and NetWbPS (=WbPS−WbPB) were measured using stable isotope methodology during 20 min of exercise (at 50% peak work load of COPD group). The controls performed a second exercise test at the same relative workload. Exercise was followed by 1 h of recovery. In the healthy group, WbPS, SPE, and NetPS were higher during casein than during whey feeding (P<.01). WbPS and NetPS were higher during exercise, independent of exercise intensity (P<.01). NetPS was higher during casein feeding in COPD due to lower WbPB (P<.05). Higher SPE was found during exercise during casein and whey feeding in COPD (P<.05). Lactate levels during exercise were higher in COPD (P<.05) independent of the protein. Post-exercise, lower NetPS values were found independent of protein type in both groups. Casein resulted in more protein anabolism than whey protein which was maintained during and following exercise in COPD. Optimizing protein intake might be of importance for muscle maintenance during daily physical activities in COPD.

Purified fish oil eliminating linoleic and alpha linolenic acid meets essential fatty acid requirements in rats - Corrected Proof

Pei-Ra Ling, Mark Puder, Bruce R. Bistrian — 2012-04-18

Abstract: This study examined whether purified fish oil (PFO) supplemented to an essential fatty acid deficient (EFAD) diet meets EFA needs in rats. The EFAD diet contained 10% hydrogenated coconut oil (HCO). A similar diet contained 7% HCO and 3% PFO which also provided 2.84% arachidonic acid (AA), 52.50% eicosapentaenoic acid (EPA) and 35.73% docosahexaenoic acid (DHA) but no linoleic acid (LA) or alpha linolenic acid (ALA). A 10% soybean oil control diet provided ample LA and ALA. After 4 weeks of feeding, blood glucose, plasma triglyceride and phospholipid fatty acid profiles, C-reactive protein (CRP), TNF and IL-6 were determined after saline or LPS injection. EFAD developed with the HCO diet with triene:tetraene ratios in plasma phospholipids >.20, which remained <.02 with the control and HCO+PFO diets. Mead acid levels significantly increased by a factor of 10 with the HCO diet compared to the AIN and HCO+PFO diets and were significantly lowest with the HCO+PFO diet. 18:1 n9 levels were significantly higher in plasma phospholipids and triglycerides with the HCO diet. CRP levels were significantly highest with the control diet and significantly lowest with the HCO diet. LPS significantly increased 18:1n9 and cytokines, and decreased AA and plasma glucose in all diets and significantly increased plasma triglycerides and decreased plasma glucose in controls. Providing AA, EPA and DHA in EFAD prevents EFAD over the short-term as reflected in Mead acid production, triene:tetraene ratio, and de novo lipogenesis and may reduce the inflammatory response to LPS.

Determinants of ApoB, ApoA1, and the ApoB/ApoA1 ratio in healthy schoolgirls, prospectively studied from mean ages 10 to 19 years: the Cincinnati National Growth and Health Study - Corrected Proof

John A. Morrison, Charles J. Glueck, Stephen R. Daniels, Paul S. Horn, Ping Wang — 2012-04-18

Abstract: The objectives were to prospectively assess determinants of apolipoproteins B (ApoB), A1 (ApoA1), and the ApoB/ApoA1 ratio in 797 healthy black and white schoolgirls from mean ages 10 to 19. There was prospective 9-year follow-up, with measures of ApoB at mean ages 10, 12, 14, 16 and 19, ApoA1 at mean ages 12, 14, 16, and 19, and assessment of annual reports of delayed menstrual cyclicity (≥42 days) from ages 14 to 19. Studies of 402 black and 395 white healthy schoolgirls were done in public and private schools, in urban and suburban Cincinnati. Black girls had lower ApoB, higher ApoA1, and lower ApoB/ApoA1. SHBG at age 14 in white and black girls was inversely correlated with the ApoB/ApoA1. At age 19, ≥3 annual reports of menstrual delay ≥42 days and metabolic syndrome were associated with higher ApoB and a higher ApoB/ApoA1 ratio. From ages 14 to 19, BMI and TG were independently positively associated with ApoB. Menstrual cyclicity ≥42 days, metabolic syndrome, BMI, and TG were independently positively associated with ApoB/ApoA1 ratios, while black race was negatively associated. The atherogenic ApoB/ApoA1 ratio from ages 14 to 19 is lower in black girls, and positively associated with hyperandrogenism, menstrual cyclicity ≥42 days, BMI, TG, and the metabolic syndrome, facilitating an adolescent approach to primary prevention of cardiovascular disease.

Estrogen mediation of hormone responses to exercise - Corrected Proof

Robert R. Kraemer, Michelle Francois, V. Daniel Castracane — 2012-04-18

Abstract: The roles of estrogens extend from the regulation of reproduction to other functions involved in control of metabolism, fluid balance, as well as gastrointestinal, lung, and brain function, with a strong effect on other hormones that subsequently alter the physiology of multiple tissues. As such, alteration of endogenous estrogens across the menstrual cycle, or from oral contraception and estrogen replacement therapy, can affect these tissues. Due to the important effects that estrogens have on different tissues, there are many investigations concerning the effects of a human estrogenic environment on endocrine responses to exercise. The following review will describe the consequences of varying estrogen levels on pituitary, adrenal, gonadal, and endocrine function, followed by discussion of the outcomes of different estrogen levels on endocrine tissues in response to exercise, problems encountered for interpretation of findings, and recommended direction for future research.

Promoting only the consumption of healthy foods may be an alternative stategy for treating patients with the metabolic syndrome - Corrected Proof

2012-04-16

Abstract: Objective: To evaluate the effectiveness of two lifestyle, interventional approaches on metabolic abnormalities and eating habits of patients with metabolic syndrome.Materials/Methods: This is a randomized controlled trial, involving a 6-month lifestyle intervention. Eighty-eight metabolic syndrome patients were randomized to one of the three groups: (i) “Increase - Decrease” group, (ii) “Increase” group, and (iii) “Minimum intervention” group. All patients received dietary and physical activity advice at baseline; patients in the first two groups also participated in individual counseling sessions. In the “Increase - Decrease” group, all recommended dietary and physical activity goals were targeted, whereas in the “Increase” group, only goals proposing an increase in dietary intake or physical activity were included. Patients received nutrition counseling through seven, one-to-one sessions, conducted every two weeks for the first 2 months, every month for the following 4 months. All participants underwent a full medical and nutritional assessment at baseline and at the end of the intervention.Results: At 6 months, BMI and waist circumference were improved in the “Increase” and the “Increase - Decrease” groups, compared to the “Minimum Intervention” group. Additionally, “Increase - Decrease” group reduced blood systolic (p=0.017), diastolic pressure (p=0.005) and glucose concentrations (p=0.015). Forty eight percent, 32%, and 19% of the patients in the “Increase - Decrease”, “Increase” and “Minimum Intervention” groups, respectively, ceased to fulfill the criteria for the metabolic syndrome (p=0.031).Conclusions: Promoting only the increase of the intake of healthy foods did not result in better outcome values compared to a conventional all-food approach.

Vascular effects of intravenous intralipid and dextrose infusions in obese subjects - Corrected Proof

2012-04-09

Abstract: Hyperglycemia and elevated free fatty acids (FFA) are implicated in the development of endothelial dysfunction. Infusion of soy-bean oil-based lipid emulsion (Intralipid®) increases FFA levels and results in elevation of blood pressure (BP) and endothelial dysfunction in obese healthy subjects. The effects of combined hyperglycemia and high FFA on BP, endothelial function and carbohydrate metabolism are not known. Twelve obese healthy subjects received four random, 8-h IV infusions of saline, Intralipid 40 mL/h, Dextrose 10% 40 mL/h, or combined Intralipid and dextrose. Plasma levels of FFA increased by 1.03±0.34 mmol/L (p=0.009) after Intralipid, but FFAs remained unchanged during saline, dextrose, and combined Intralipid and dextrose infusion. Plasma glucose and insulin concentrations significantly increased after dextrose and combined Intralipid and dextrose (all, p<0.05) and were not different from baseline during saline and lipid infusion. Intralipid increased systolic BP by 12±9 mmHg (p<0.001) and diastolic BP by 5±6 mmHg (p=0.022),and decreased flow-mediated dilatation (FMD) from baseline by 3.2%±1.4% (p<0.001). Saline and dextrose infusion had neutral effects on BP and FMD. The co-administration of lipid and dextrose decreased FMD by 2.4%±2.1% (p=0.002) from baseline, but did not significantly increase systolic or diastolic BP. Short-term Intralipid infusion significantly increased FFA and BP; in contrast, FFA and BP were unchanged during combined infusion of Intralipid and dextrose. Combined Intralipid and dextrose infusion resulted in endothelial dysfunction similar to Intralipid alone.

Adding sprints to continuous exercise at the intensity that maximises fat oxidation: Implications for acute energy balance and enjoyment - Corrected Proof

2012-04-05

Abstract: The objective was to examine the effect of adding sprints to continuous exercise at the intensity that maximises fat oxidation (Fatmax) on energy expenditure, substrate oxidation, enjoyment and post-exercise energy intake in boys. Nine overweight and nine normal weight boys (8–12 years) attended the laboratory on three mornings. First, body anthropometrics, peak aerobic capacity and Fatmax were assessed. On the remaining two sessions, resting metabolic rate was determined before participants completed 30 min of either continuous cycling at Fatmax (MOD) or sprint interval exercise consisting of continuous cycling at Fatmax interspersed with four-second maximal sprints every two minutes (SI). Energy expenditure and substrate oxidation were measured during exercise and for 30 min post-exercise, while participants completed a modified Physical Activity Enjoyment Scale (PACES). This was followed by a buffet-like breakfast to measure post-exercise energy intake. Fat oxidation rate was similar between groups and protocols (P>0.05). Both groups expended more energy with SI compared to MOD, resulting from increased carbohydrate oxidation (P<0.05), which was not compensated by increased energy intake. Participants indicated that they preferred SI more than MOD, although there was no significant difference in PACES score between the protocols (P>0.05). In summary, the addition of short sprints to continuous exercise at Fatmax increased energy expenditure without compromising fat oxidation or stimulating increased post-exercise energy intake. The boys preferred SI and did not perceive it to be any harder than MOD, indicating that sprint interval exercise should be considered in exercise prescription for this population.

Changes of metabolic and inflammatory markers in HIV infection: glucose, lipids, serum Hs-CRP and myeloperoxidase - Corrected Proof

2012-04-05

Abstract: Objective: HIV infection is exacerbated through additional pro-atherogenic mechanisms related to the processes of immune activation, inflammation, coagulation, and the modification of lipoproteins (e.g., particles of high density lipoprotein), contributing to increased cardiovascular risk. The aim of this study was to analyze the serum concentrations of myeloperoxidase (MPO) and other laboratory parameters in HIV-infected patients treated or not with antiretroviral drugs compared to non-infected individuals.Materials/Methods: The study included 154 volunteers: 47 non-infected individuals (control group - CON), 27 infected and untreated individuals (NTARV group) and 80 treated individuals (TARV group). We analyzed the counts of CD4+ lymphocytes and the viral load of the infected patients, along with the blood count, fasting glucose, total serum cholesterol (CHOL), HDL cholesterol, LDL cholesterol, triglycerides, MPO and high-sensitivity C-reactive protein (CRP) of all study participants.Results: There were significant increases in glucose, CHOL, LDL cholesterol, and triglycerides in the TARV group and significant reductions in the levels of HDL cholesterol for the TARV and NTARV groups. Significantly elevated levels of Hs-CRP were observed only in the TARV group, while levels of MPO were significantly higher in the TARV and NTARV groups compared to the control group. A correlation of MPO with Hs-CRP (r=0.21, p=0.032) was observed for HIV-infected patients, but MPO did not correlate significantly with the other analyzed parameters.Conclusions: The investigation of early biomarkers for cardiovascular risk evaluation, such as MPO, contributes to the clinical monitoring of HIV-infected individuals. The serum levels of MPO correlated with Hs-CRP and were high in HIV-infected individuals, indicating a possible predictor of cardiovascular events in these patients.

Over-nutrition and metabolic cardiomyopathy - Corrected Proof

Chirag H. Mandavia, Lakshmi Pulakat, Vincent DeMarco, James R. Sowers — 2012-04-01

Abstract: Cardiovascular disease, which accounts for the highest morbidity and mortality in the United States, has several major risk factors, including aging and diabetes. Overweight and obesity, especially abdominal obesity, have been increasingly implicated as independent risk factors in the development of cardiovascular disease. Metabolic and/or diabetic cardiomyopathy has been especially associated with excess body weight caused by chronic over-nutrition and high-fat feeding. In the initial stages, obesity is now understood to cause significant dysregulation of cardiac fatty acid and glucose metabolism. These abnormalities are due, in part, to increased oxidative stress, which in turn can cause deleterious effects on intracellular signaling pathways that control cellular growth and proliferation. This increase in oxidative stress is coupled with reduced anti-oxidant species and dysregulation of metabolic signaling pathways. The cardiomyopathy seen with obesity is associated with increased interstitial fibrosis and diastolic dysfunction. Over time, evolving abnormalities include hypertrophy and systolic dysfunction, eventually leading to heart failure.

CYP1B1 Asn453Ser polymorphism and colorectal cancer risk: a meta-analysis - Corrected Proof

Qiang Mei, Daijun Zhou, Jialong Han, Hai Lu, Bo Tang — 2012-03-30

Abstract: Studies investigating the association between cytochrome P450 1B1 (CYP1B1) Asn453Ser (453 A/G, rs1800440) polymorphism and colorectal cancer (CRC) risk report conflicting results. The aim of this study was to quantitatively summarize the evidence for such a relationship. Two investigators independently searched the Medline and Embase Databases. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP1B1 polymorphism and CRC were calculated in a fixed-effects model (the Mantel–Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. The pooled ORs were performed for co-dominant model (GG vs AA, GA vs AA), dominant model (GG+GA vs AA), and recessive model (GG vs GA+AA). This meta-analysis included 7 case-control studies, which included 6375 CRC cases and 7003 controls. Overall, the variant genotypes (GG and GA) of the 453 A/G were not associated with CRC risk when compared with the wild-type AA homozygote (GG vs AA, OR=0.94, 95% CI=0.77–1.14; GA vs AA, OR=0.99, 95% CI=0.87–1.12). Similarly, no associations were found in the dominant and recessive models (dominant model, OR=0.98, 95% CI=0.87–1.09; recessive model, OR=0.94, 95% CI=0.77–1.14). When stratifying for country, study sample size, matched control and source of controls, no evidence of significant association was observed in any subgroup, except among those studies from “Canada”. No publication bias was found in the present study. No association was found between the CYP1B1 Asn453Ser polymorphism and risk of CRC among Caucasians.

A cross-over study of the acute effects of espresso coffee on glucose tolerance and insulin sensitivity in people with type 2 diabetes mellitus - Corrected Proof

2012-03-29

Abstract: The objective was to determine the effect of a single dose of espresso caffeinated coffee, decaffeinated coffee, or water on glucose tolerance and insulin sensitivity in people with type 2 diabetes mellitus. Eighteen participants who were habitual coffee drinkers, were studied using a random-order cross-over design. After a fasting blood sample participants consumed either a double-shot black espresso coffee, decaffeinated coffee, or hot water. The main outcomes were area under the curve (AUC) glucose and insulin, and insulin sensitivity (Matsuda index) during a 75 g oral glucose tolerance test (OGTT) performed one hour later. Other outcomes were change in glucose and insulin and also the insulinogenic index (IGI) and disposition index (DI). AUC glucose was marginally different between beverages (P=.06) being greater following caffeinated coffee than water, mean difference 104 mmol/L/180 min (95% CI 0.1 to 198.1, P=.031), or decaffeinated coffee, mean difference 92.1 mmol/L/180 min (95% CI −1.9 to 186.1, P=.055). There was no difference in AUC insulin (P=.87) or insulin sensitivity (P=.47), nor in change in glucose or insulin over the hour following beverage consumption. There was a marginal difference in IGI between beverages (P=.097) with coffee having a lower incremental increase in insulin/glucose than water (P=.037) though no difference between coffee and decaffeinated coffee (P=.54) and no difference in DI (P=.23). Black espresso coffee in people with type 2 diabetes mellitus results in a marginally greater excursion of glucose during a following OGTT compared with water or decaffeinated coffee. This effect does not appear to be mediated by changes in insulin sensitivity.

Intestinal fatty acid infusion modulates food preference as well as calorie intake via the vagal nerve and midbrain–hypothalamic neural pathways in rats - Corrected Proof

2012-03-27

Abstract: The intestine plays important roles in the regulation of feeding behavior by sensing macronutrients. Intestinal fatty acids strongly suppress food intake, but little is known about whether intestinal fatty acids affect food preference. We investigated the effects of jejunal fatty acids infusion on food preference by conducting two-diet choice experiments in rats fed a high-fat diet (HFD) and a high-carbohydrate diet (HCD). Jejunal linoleic acid (18:2) infusion reduced HFD intake dose-dependently, while HCD intake increased with the middle dose of the infusion we examined (100 μL/h) and reduced to the control level with the higher doses (150 and 200 μL/h). α-Linolenic acid (18:3), but not caprylic acid (8:0), altered the food preference and total calorie intake in the same manner as linoleic acid. Linoleic acid infusion dose-dependently increased plasma glucagon-like peptide-1, peptide YY and cholecystokinin levels, but not ghrelin levels. Subdiaphragmatic vagotomy or midbrain transection prevented the change in food preference and total calorie intake by linoleic acid infusion. Jejunal linoleic acid infusion increased norepinephrine turnover in the paraventricular hypothalamic nucleus, while intracerebroventricular injection of idazoxan, an α2-adrenergic receptor (AR) antagonist, suppressed the increased HCD intake, but did not affect the decreased HFD intake. These findings indicated that intestinal long-chain fatty acids modulated food preference as well as total calorie intake via the vagal nerve and midbrain–hypothalamic neural pathways. The effects of the α2-AR antagonist in the brain suggested that the brain distinctly controlled HCD and HFD intake in response to jejunal linoleic acid infusion.

Polymorphisms of POR, SULT2A1 and HSD11B1 in children with premature adrenarche - Corrected Proof

Pauliina Utriainen, Saila Laakso, Jarmo Jääskeläinen, Raimo Voutilainen — 2012-03-26

Abstract: Premature adrenarche (PA) refers to an earlier than normal increase in adrenocortical androgen production. The pathogenesis of PA remains largely unknown. We hypothesized that common polymorphisms at P450 oxidoreductase (POR), steroid sulfotransferase (SULT2A1), or 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) genes could contribute to the polygenic pathogenesis of PA. We performed a case–control study on the polymorphisms rs1057868 at POR, rs182420 at SULT2A1, and rs12086634 at HSD11B1. The study cohort comprised 73 prepubertal children with PA (defined by clinical signs) and 97 age- and gender-matched healthy controls from a Finnish Caucasian population. Genotype distributions and clinical and metabolic phenotypes were determined. The genotype distributions of the polymorphisms were similar between the study groups. No variant was associated with alterations in serum adrenal steroid concentrations. The minor C variant at SULT2A1 was associated with higher serum sex hormone binding globulin (SHBG) concentrations (T/T, n=64 vs T/C&C/C, n=33; mean 94 vs 116 nmol/L; P=.001) and a trend for lower dehydroepiandrosterone sulfate/dehydroepiandrosterone ratios in the controls (P=.06), and with higher plasma total cholesterol concentrations in the PA subjects (T/T, n=42 vs T/C&C/C, n=31; 4.0 vs 4.6 mmol/L; P<.001). The minor G variant at HSD11B1 was associated with lower plasma triglyceride concentration in the controls (T/T, n=65 vs T/G&G/G, n=32; 0.61 vs 0.49 mmol/L; P=.013). Common polymorphisms at POR, SULT2A1 or HSD11B1 were not associated with PA in a Finnish Caucasian population.

Fatty acid flux and oxidation are increased by rimonabant in obese women - Corrected Proof

2012-03-26

Abstract: This study aimed to determine in obese women if endocannabinoid receptor antagonism has effects on fatty acid and triglyceride metabolism and insulin sensitivity which are independent from the metabolic effects of weight loss. Fourteen obese (BMI=33.0±0.5 kg/m2) (mean±SEM) Caucasian post-menopausal women, aged 57.8±4.7 years were studied. The women were randomised to 2 groups, one group received the endocannabinoid receptor antagonist rimonabant (20 mg/d) for 12 weeks. A control group achieved the same weight loss by a hypocaloric dietary intervention over 12 weeks. Palmitate production rate (Ra), a measure of lipolysis, and palmitate oxidation rate, and VLDL1 and VLDL2 triglyceride (TG) kinetics, were measured using isotopic tracers before and after the intervention. Weight loss was not different in the 2 groups; 2.6±0.5 kg with rimonabant and 3.1±1.0 kg in the control group. Palmitate Ra increased with rimonabant with no change in the control group (p=0.03 between groups). Palmitate oxidation rate increased with rimonabant but decreased in the control group (p=0.005 between groups). VLDL1 TG secretion rate decreased in the control group and increased in the rimonabant group (p=0.008 between groups). There was no significant effect on insulin sensitivity. This study suggests that endocannabinoid receptor antagonism for 12 weeks in obese women increased lipolysis and fatty acid oxidation. The increase in VLDL1 TG secretion rate may be due to the increase in lipolysis which exceeded the increase in fatty acid oxidation.

A randomized trial of copper supplementation effects on blood copper enzyme activities and parameters related to cardiovascular health - Corrected Proof

2012-03-23

Abstract: Marginal copper deficiency, which may affect cardiovascular disease risk, is proposed to occur in many adults in Western industrialized countries. The present study tested the hypothesis that in a group of USA adults, increased copper intake would alter readings for blood copper enzymes and markers relevant to cardiovascular disease risk. Healthy middle aged adults with moderately high cholesterol, were given either placebo or copper supplementation (2 mg copper/day as copper glycinate) for 8 weeks. Blood samples were taken before and after the 8 weeks. Copper, but not placebo, raised activities for two copper enzymes, erythrocyte superoxide dismutase 1 and plasma ceruloplasmin. In contrast, five cardiovascular health related plasma parameters were not changed significantly by copper: C-reactive protein, homocysteine, and cholesterol (total, LDL and HDL). However, changes in erythrocyte superoxide dismutase 1 correlated positively with changes in plasma HDL and negatively with plasma homocysteine. Also, copper lowered mean oxidized LDL values, a result that was statistically significant, but inconsistent. In this test population, increased copper intake raised copper enzyme activities, but did not consistently improve the cardiovascular health measures studied.

Race–ethnic differences in adipokine levels: the Study of Women's Health Across the Nation (SWAN) - Corrected Proof

2012-03-23

Abstract: Diffferences in adipose tissue secretory profile, as measured by adipokine levels, may play a role in race–ethnic disparities in cardiovascular disease (CVD). We examined race–ethnic differences in adipokine levels in a group of mid-life Caucasian, African American (AA), Chinese and Japanese women, after accounting for adiposity. Data on 1876 women from the Study of Women’s Health Across the Nation were analyzed. In multivariable adjustment, including total fat mass, differences in total and high molecular weight (HMW) adiponectin, leptin and soluble leptin receptor (sOB-R) levels were examined. Despite intermediate levels of adiposity, Caucasian women had higher levels of both total and HMW adiponectin, when compared to both AA and Chinese and Japanese women. After multivariable adjustment, compared to Caucasian women, AA women had significantly lower total (β: −3.40; 95% CI: −4.29, −2.52; P<.001) and HMW adiponectin (β: −0.53; 95% CI: −0.64, −0.43; P<.001) levels, higher leptin levels (β: 3.26; 95% CI: 1.36, 5.16; P<.001) and lower sOB-R levels (β: −0.07; 95% CI: −0.11, −0.03; P<.001). Compared to Caucasian women, both Chinese and Japanese women had lower total (Chinese: β: −5.50; 95% CI: −7.07, −3.93; P<.001; Japanese: β: −5.48; 95% CI: −6.95, −4.02; P<.001) and HMW adiponectin (Chinese: β: −0.57; 95% CI: −0.75, −0.38; P<.001; Japanese: β: −0.61; 95% CI: −0.78, −0.44; P<.001) levels and lower sOB-R levels (Chinese: β: −0.13; 95% CI: −0.20, −0.06; P<.001; Japanese: β: −0.09; 95% CI: −0.15, −0.02; P=.008). Significant race–ethnic differences exist in circulating adipokines, even after accounting for adiposity. Further research is needed to explicitly determine if such differences contribute to known racial differences in CVD risk.

Influence of obesity indices, metabolic parameters and age on cardiac autonomic function in abdominally obese men - Corrected Proof

2012-03-23

Abstract: Heart rate variability (HRV) is affected by age, hyperglycemia and accumulation of body fat. This study compares the predictive value of four measurements of adiposity/obesity on HRV and investigates the specific role of age, metabolic contributors and degree/distribution of fat in HRV alterations. The sample consisted of 97 non-diabetic and non-medicated men with features of the metabolic syndrome (50±8 years of age, body mass index [BMI] 31±3 kg/m2, waist circumference [WC] 107±9 cm, triglycerides 2.3±0.7 mmol/L, fasting glucose 6.0±0.5 mmol/L, insulin 156±71 pmol/L; mean±SD). WC, BMI, percent body fat (% fat, from dual energy X-ray absorptiometry) and visceral adipose tissue volume (VAT, from computed tomography) were used as measures of adiposity/obesity. HRV measures were obtained from 24-h, day- and night-time segments of Holter recordings. BMI presented no independent association with HRV. Percentage fat was the strongest obesity index to be associated with HRV: 24-h pNN50, rMSSD, HF and daytime pNN50, rMSSD, HF and LF (−0.27≤std β≤−0.20, P<.05). VAT was associated with 24-h SDNN, LF (std β=−0.25 and −0.20, P<.05, respectively) and daytime SDNN (std β=−0.24, P<.05) while WC was associated with nighttime SDNN and SDANN (std β=0.22 and 0.32, P<.05). In addition, age, fasting glucose, 2-h oral glucose tolerance test and triglycerides presented independent association with HRV. Adiposity/obesity measurements seem to be differently associated with HRV. An approach considering the combination of age, obesity and glucose metabolism factors could be helpful in the global cardiovascular risk management in abdominally obese men.

Hypothyroidism: age-related influence on cardiovascular nitric oxide system in rats - Corrected Proof

2012-03-19

Abstract: This study investigates whether changes in nitric oxide (NO) production participate in the cardiovascular manifestations of hypothyroidism and whether these changes are age-related. Sprague–Dawley rats aged 2 and 18 months old were treated with 0.02% methimazole (wt/vol) during 28 days. Left ventricular function was evaluated by echocardiography. Measurements of arterial blood pressure, heart rate, nitric oxide synthase (NOS) activity and NOS/caveolin-1 and -3 protein levels were performed. Hypothyroidism enhanced the age-related changes in heart function. Hypothyroid state decreased atrial NOS activity in both young and adult rats, associated with a reduction in protein levels of the three NOS isoforms in young animals and increased caveolin (cav) 1 expression in adult rats. Ventricle and aorta NOS activity increased in young and adult hypothyroid animals. In ventricle, changes in NOS activity were accompanied by an increase in inducible NOS isoform in young rats and by an increase in caveolins expression in adult rats. Greater aorta NOS activity level in young and in adult Hypo rats would derive from the inducible and the endothelial NOS isoform, respectively. Thyroid hormones would be one of the factors involved in the modulation of cardiovascular NO production and caveolin-1 and -3 tissue-specific abundance, regardless of age. Hypothyroidism appears to contribute in a differential way to aging-induced changes in the myocardium and aorta tissues. Low thyroid hormones levels would enhance the aging effect on the heart. Age-related changes in NO production participate in the cardiovascular manifestations of hypothyroidism.

Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial - Corrected Proof

2012-03-19

Abstract: The objective was to determine the effect of metformin on the concentrations of resistin and other markers of insulin resistance or inflammation (C-reactive protein, cytokines, body weight, HbA1c, among others) in minors with glucose intolerance. Patients aged 4 to 17 years with glucose intolerance were studied. They were randomized to receive 850 mg of either metformin or placebo twice daily for 12 weeks, during which all followed an iso-caloric diet and an exercise program. High sensitivity C-reactive protein, TNF-alpha, IL-6, IL1-beta, resistin, leptin, adiponectin, glucose, insulin, HbA1c, lipid profile and transaminases were measured at the beginning and at the end of the period. Fifty-two patients were included, 11.9±2.6 years old; 28 (12 males/16 females) received metformin and 24 placebo (11 males/13 females). Baseline characteristics were similar between groups (except for body mass index, which in the metformin group was slightly higher). Percentage weight loss was greater in the metformin group (−5.86% vs 2.75%, P<.05). At study end, there were statistically significant differences in resistin concentrations, even after adjusting for confounding variables (F=7.714; P<.006). Also, metformin was associated with a significant decrease in HOMA-IR index (P=.032) and HbA1c levels (P=.001), but no change was observed in the concentration of other markers of inflammation. Metformin resulted in significant reductions of plasma resistin levels in minors with glucose intolerance. This change is independent of its effects on body weight. In contrast, metformin did not alter the concentration of inflammatory markers.

Lean mass and insulin resistance in women with polycystic ovary syndrome - Corrected Proof

Kevin B. Comerford, Rogelio U. Almario, Kyoungmi Kim, Sidika E. Karakas — 2012-03-19

Abstract: Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Muscle is the major tissue utilizing glucose while excess adipose tissue relates to insulin resistance. Thus, body composition is likely to be an important regulator of insulin sensitivity. Thirty-nine PCOS patients (age: 29.9±1.0 years; BMI: 33.8±1.2 kg/m2) participated in a cross sectional study. Body composition was measured by dual energy x-ray absorptiometry (DEXA). Insulin resistance and secretion were assessed using oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FS-IVGTT). In contrast with the conventional expectations, lean mass correlated directly (P<.05) with the insulin resistance measure HOMA (r=0.440); and inversely with the insulin sensitivity index QUICKI (r=−0.522) independent of fat mass. In 11 pairs of subjects matched for fat mass (35.6±2.2 and 35.6±2.4 kg) but with discordant lean mass (52.8±1.8 vs 44.4±1.6 kg), those with higher lean mass had a higher glucose response during OGTT (AUCGlucose; P=.034). In contrast, 17 pairs matched for lean mass (48.7±1.7 and 48.9±1.6 kg) but discordant for fat mass (43.3±2.6 vs 30.3±8.9 kg) showed no differences in insulin resistance parameters. These novel findings indicate that lean mass relates directly to insulin resistance in PCOS.

Elevated IgG levels against specific bacterial antigens in obese patients with diabetes and in mice with diet-induced obesity and glucose intolerance - Corrected Proof

Nadeem Mohammed, Lihua Tang, Anisa Jahangiri, Willem de Villiers, Erik Eckhardt — 2012-03-19

Abstract: High fat diets increase the risk for insulin resistance by promoting inflammation. The cause of inflammation is unclear, but germfree mouse studies have implicated commensal gut bacteria. We tested whether diet-induced obesity, diabetes, and inflammation are associated with anti-bacterial IgG. Blood from lean and obese healthy volunteers or obese patients with diabetes were analyzed by ELISA for IgG against extracts of potentially pathogenic and pro-biotic strains of Escherichia coli (LF-82 and Nissle), Bacteroides thetaiotaomicron, and Lactobacillus acidophilus, and for circulating tumor necrosis factor α (TNFα). C57Bl/6 mice were fed low- or high-fat diets (10% or 60% kcal from fat) for 10 weeks and tested for anti-bacterial IgG, bodyweight, fasting glucose, and inflammation. Obese diabetic patients had significantly more IgG against extracts of E. coli LF-82 compared with lean controls, whereas IgG against extracts of the other bacteria was unchanged. Circulating TNFα was elevated and correlated with IgG against the LF-82 extract. Mice fed high-fat diets had increased fasting glucose levels, elevated TNFα and neutrophils, and significantly more IgG against the LF-82 extracts. Diabetes in obesity is characterized by increased IgG against specific bacterial antigens. Specific commensal bacteria may mediate inflammatory effects of high-fat diets.

Carbohydrate supplementation increases intramyocellular lipid stores in elite runners - Corrected Proof

2012-03-14

Abstract: The objective was to determine the effects of carbohydrate (CHO) supplementation on exercise-induced hormone responses and post-training intramyocellular lipid stores (IMCL). Twenty-four elite male athletes (28.0±1.2 years) were randomized to receive CHO (maltodextrin solution) or zero energy placebo solution (control group). The high-intensity running protocol consisted of 10×800 m at 100% of the best 3000-m speed (Vm3 km) and 2×1000 m maximal bouts in the morning and a submaximal 10-km continuous easy running in the afternoon of day 9. IMCL concentrations were assessed by 1H-MRS before (−day 9) and after training (day 9) in soleus (SO) and tibialis anterior (TA) muscles. Blood hormones were also measured before, during, and post-exercise. The percent change (Δ%) in TA-IMCL was higher in the CHO group (47.9±24.5 IMCL/Cr) than in the control group (−1.7±13.1, respectively) (P=.04). Insulin concentrations were higher in the CHO group post-intermittent running compared to control (P=.02). Circulating levels of free fatty acids and GH were lower in the CHO group (P>.01). The decline in performance in the 2nd 1000-m bout was also attenuated in this group compared to control (P<.001 and P=.0035, respectively). The hormonal milieu (higher insulin and lower GH levels) in the CHO group, together with unchanged free fatty acid levels, probably contributed to the increased IMCL stores. This greater energy storage capacity may have improved post-exercise recovery and thus prevented performance deterioration.

Association between hippocampal volume and serum adiponectin in patients with type 2 diabetes mellitus - Corrected Proof

2012-03-12

Abstract: Type 2 diabetes mellitus (DM) is associated with cognitive dysfunction and hippocampus volume. The aim of the present study was to test the hypothesis that the level of the adipocytokine adiponectin correlates with hippocampus volume and insulin resistance in patients with type 2 DM. A total of 45 patients with type 2 DM were divided into two groups: a low adiponectin group and a normal adiponectin group. Hippocampus volume was measured by computer-assisted analysis using a magnetic resonance imaging (MRI) voxel-based specific regional analysis system developed for the study of Alzheimer's disease as the end point for assessment of hippocampus volume. Mean hippocampus volume was lower in the low adiponectin group than in the normal adiponectin group (P<.0001). Fasting serum concentrations of glucose (P<.05) and insulin (P<.0001), and homeostasis model assessment index (P<.0001), were all higher in the low adiponectin group than in the normal adiponectin group. Multiple regression analysis showed that hippocampus volume independently predicted serum adiponectin level. These results suggest that circulating levels of adiponectin are related to hippocampus volume in patients with type 2 DM.

Sex differences in the effect of high-fat diet feeding on rat white adipose tissue mitochondrial function and insulin sensitivity - Corrected Proof

Emilia Amengual-Cladera, Isabel Lladó, Magdalena Gianotti, Ana M. Proenza — 2012-03-09

Abstract: Obesity-induced mitochondrial dysfunction in white adipose tissue (WAT) leads to a dysregulation of adipokine secretion, which is involved in insulin resistance development. Taking into account the sex differences previously found both in mitochondrial function and for the insulin sensitivity profile in different tissues, the aim of this study was to investigate whether a sex-dependent effect of a long-term high-fat diet (HFD) feeding exists on WAT mitochondrial function. Indeed, HFD effects on the levels of the key components of the insulin and adiponectin signaling pathways, and the consequences of these effects on the systemic profile of insulin sensitivity were also studied. Wistar rats of both sexes were fed a standard diet or an HFD. Serum markers of insulin sensitivity, protein, and mRNA levels of the main elements of the insulin and adiponectin signaling pathways, and the markers of mitochondrial function and biogenesis, were measured. Our results indicate that different physiological strategies are adopted by male and female rats in response to HFD. In this regard, HFD induced mitochondrial proliferation in males and mitochondrial differentiation in females, as well as a greater retroperitoneal WAT expandability capacity, which allows them to preserve a better insulin sensitivity profile than male rats for both control and HFD groups. Moreover, female WAT showed a decrease in adiponectin and insulin signaling pathway element levels. This sexual dimorphism suggests that there are different strategies for retroperitoneal WAT to maintain the energetic and metabolic homeostasis in response to HFD feeding.

Erratum - Corrected Proof

2012-03-09

In the article “Stronger associations of sagittal abdominal diameter with atherogenic lipoprotein subfractions than waist circumference in middle-aged US white and Japanese men” by Nakata et al (Metabolism 2010;59:1742–51; doi:10.1016/j.metabol.2010.04.019) there is an error in Table 1. The units for VAT and SAT were reported in cm2; the correct unit is cm3 per 0.6 cm height. Dividing the value by 0.6 gives the number in cm2.

Erratum - Corrected Proof

2012-03-09

In the article “Higher liver fat content among Japanese in Japan compared with non- Hispanic whites in the US” by Azuma et al (Metabolism 2009; 58: 1200–7; doi:10.1016/j.metabol.2009.03.021), the following errors should be corrected:

The health benefits of dietary fiber: Beyond the usual suspects of type 2 diabetes mellitus, cardiovascular disease and colon cancer - Corrected Proof

Melissa M. Kaczmarczyk, Michael J. Miller, Gregory G. Freund — 2012-03-09

Abstract: Dietary fiber (DF) is deemed to be a key component in healthy eating. DF is not a static collection of undigestible plant materials that pass untouched or unencumbered through the gastrointestinal (GI) tract; instead, DFs are a vast array of complex saccharide-based molecules that can bind potential nutrients and nutrient precursors to prevent their absorption. Some DFs are fermentable, and the GI tract catabolism leads to the generation of various bioactive materials, such as short-chain fatty acids (SCFAs), that can markedly augment the GI tract biomass and change the composition of the GI tract flora. The health benefits of DFs include the prevention and mitigation of type 2 diabetes mellitus, cardiovascular disease and colon cancer. By modulating food ingestion, digestion, absorption and metabolism, DFs reduce the risk of hyperlipidemia, hypercholesterolemia and hyperglycemia. Emerging research has begun to investigate the role of DFs in immunomodulation. If substantiated, DFs could facilitate many biologic processes, including infection prevention and the improvement of mood and memory. This review describes the accepted physiologic functions of DFs and explores their new potential immune-based actions.