Intermittent Leucine Deprivation Produces Long-Lasting Improvement in Insulin Sensitivity by Increasing Hepatic Gcn2 Expression

<a>Leucine deprivation improves insulin sensitivity; however, whether and how this effect can be extended is unknown. We hypothesized that intermittent leucine deprivation (ILD) might produce a long-term effect on improved insulin sensitivity via the formation of metabolic memory. Consistently, seven ILD cycles treatment (1-day leucine-deficient diet, 3-day control diet) in mice produced a long-lasting (after resuming a control diet for 49 days) effect on improved whole-body and hepatic insulin sensitivity in mice, indicating the potential formation of metabolic memory. Furthermore, the effects of ILD depended on hepatic general control nondepressible 2 (GCN2) expression as verified by gain-and loss-of-function experiments. Moreover, ILD increased Gcn2 expression by reducing its DNA methylation at two CpG promoter sites controlled by </a><a>demethylase</a> growth arrest and DNA damage inducible b. Finally, ILD also improved insulin sensitivity in insulin-resistant mice. Thus, ILD induces long-lasting improvements in insulin sensitivity by increasing hepatic Gcn2 expression via a reduction in its DNA methylation. These results provide novel insights into understanding the link between leucine deprivation and insulin sensitivity, as well as potential nutritional intervention strategies for treating insulin resistance and related diseases. We also provide evidence for liver-specific metabolic memory after ILD and novel epigenetic mechanisms for Gcn2 regulation.

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Intermittent Leucine Deprivation Produces Long-Lasting Improvement in Insulin Sensitivity by Increasing Hepatic Gcn2 Expression

10.2337/figshare.16904041.v1 ◽

2021 ◽

Author(s):

Hanrui Yin ◽

Feixiang Yuan ◽

Fuxin Jiao ◽

Yuguo Niu ◽

Xiaoxue Jiang ◽

...

Keyword(s):

Dna Methylation ◽

Insulin Sensitivity ◽

Control Diet ◽

Nutritional Intervention ◽

Whole Body ◽

Metabolic Memory ◽

Loss Of Function ◽

Deficient Diet ◽

Insulin Resistant ◽

Potential Formation

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Hepatokine ERAP1 impairs skeletal muscle insulin sensitivity via ADRB2/PKA pathway

10.21203/rs.3.rs-37586/v1 ◽

2020 ◽

Author(s):

Feifan Guo ◽

Yuguo Niu ◽

Haizhou Jiang ◽

Hanrui Yin ◽

Fenfen Wang ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Neutralizing Antibodies ◽

Leptin Receptor ◽

Whole Body ◽

C2c12 Myotubes ◽

Insulin Resistant ◽

Skeletal Muscle Insulin Sensitivity ◽

Pka Pathway

Abstract The current study aimed to investigate the role of endoplasmic reticulum aminopeptidase 1 (ERAP1), a novel hepatokine, in whole-body glucose metabolism. Here, we found that hepatic ERAP1 levels were increased in insulin-resistant leptin-receptor-mutated (db/db) and high-fat diet (HFD)-fed mice. Consistently, hepatic ERAP1 overexpression attenuated skeletal muscle (SM) insulin sensitivity, whereas knockdown ameliorated SM insulin resistance. Furthermore, serum and hepatic ERAP1 levels were positively correlated, and recombinant mouse ERAP1 or conditioned medium with high ERAP1 content (CM-ERAP1) attenuated insulin signaling in C2C12 myotubes, and CM-ERAP1 or HFD-induced insulin resistance was blocked by ERAP1 neutralizing antibodies. Mechanistically, ERAP1 reduced ADRB2 expression and interrupted ADRB2-dependent signaling in C2C12 myotubes. Finally, ERAP1 inhibition via global knockout or the inhibitor thimerosal improved insulin sensitivity. Together, ERAP1 is a hepatokine that impairs SM and whole-body insulin sensitivity, and its inhibition might provide a therapeutic strategy for diabetes, particularly for those with SM insulin resistance.

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Zinc deficiency impairs whole body accumulation of polyunsaturates and increases the utilization of [1-14C]linoleate for de novo lipid synthesis in pregnant rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-176 ◽

1995 ◽

Vol 73 (9) ◽

pp. 1246-1252 ◽

Cited By ~ 40

Author(s):

S. C. Cunnane ◽

J. Yang

Keyword(s):

Food Intake ◽

Zinc Deficiency ◽

De Novo ◽

Control Diet ◽

Lipid Synthesis ◽

Whole Body ◽

Deficient Diet ◽

Pregnant Rats ◽

Whole Body Metabolism ◽

Zinc Deficient Diet

Zinc deficiency impairs the metabolism of polyunsaturates, but the degree to which its effects are independent of food intake are still in question. Identical amounts of a semiliquid control diet (26.4 mg zinc/kg) or moderately zinc deficient diet (3.2 mg zinc/kg) were tube fed to rats for 11 days during the second half of pregnancy to evaluate the specific effects of zinc deficiency on maternal utilization and fetal accumulation of polyunsaturates. The whole body fatty acid balance method was used to determine net accumulation of polyunsaturates and their whole-body disappearance. Incorporation of 14C from [1-14C]linoleate into maternal and fetal lipid classes was also studied on days 20–21. At term, zinc-deficient rats had significantly higher whole-body disappearance of linoleate and α-linolenate and lower accumulation of n−6 and n−3 long-chain polyunsaturates. Zinc-deficient rats had higher 14C activity in free cholesterol, saturates, and monounsaturates in several maternal organs but not in the fetuses. We conclude that during pregnancy, moderate zinc deficiency not affecting food intake or weight gain still alters whole-body metabolism of linoleate and α-linolenate towards increased β-oxidation and also increases the utilization of carbon from linoleate for de novo lipid synthesis.Key words: cholesterol, linoleate, α-linolenate, oxidation, polyunsaturates, pregnancy, zinc.

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Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00846.2004 ◽

2005 ◽

Vol 289 (2) ◽

pp. R486-R494 ◽

Cited By ~ 101

Author(s):

Andrea S. Rossi ◽

Yolanda B. Lombardo ◽

Jean-Marc Lacorte ◽

Adriana G. Chicco ◽

Christine Rouault ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Fish Oil ◽

Essential Role ◽

Control Diet ◽

Insulin Resistant ◽

Dietary Fish ◽

Plasma Leptin

Insulin resistance and adiposity induced by a long-term sucrose-rich diet (SRD) in rats could be reversed by fish oil (FO). Regulation of plasma leptin and adiponectin levels, as well as their gene expression, by FO might be implicated in these findings. This study was designed to evaluate the long-term regulation of leptin and adiponectin by dietary FO in a dietary model of insulin resistance induced by long-term SRD in rats and to determine their impact on adiposity and insulin sensitivity. Rats were randomized to consume a control diet (CD; n = 25) or an SRD ( n = 50) for 7 mo. Subsequently, the SRD-fed rats were randomized to consume SRD+FO or to continue on SRD for an additional 2 mo. Long-term SRD induced overweight and decreased both plasma leptin and adiponectin levels without change in gene expression. Dyslipidemia, adiposity, and insulin resistance accompanied these modifications. Shifting the source of fat to FO for 2 mo increased plasma levels of both adipokines, reversed insulin resistance and dyslipidemia, and improved adiposity. These results were not associated with modifications in gene expression. These results suggest that increasing both adipokines by dietary FO might play an essential role in the normalization of insulin resistance and adiposity in dietary-induced, insulin-resistant models.

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Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00155.2004 ◽

2004 ◽

Vol 287 (4) ◽

pp. E799-E803 ◽

Cited By ~ 18

Author(s):

Gina B. Di Gregorio ◽

Rickard Westergren ◽

Sven Enerback ◽

Tong Lu ◽

Philip A. Kern

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Tolerance Test ◽

Intravenous Glucose Tolerance Test ◽

Whole Body ◽

Forkhead Transcription Factor ◽

Intravenous Glucose ◽

Insulin Resistant ◽

Diet Induced Obesity ◽

Tnf Α

FOXC2 is a winged helix/forkhead transcription factor involved in PKA signaling. Overexpression of FOXC2 in the adipose tissue of transgenic mice protected against diet-induced obesity and insulin resistance. We examined the expression of FOXC2 in fat and muscle of nondiabetic humans with varying obesity and insulin sensitivity. There was no relation between body mass index (BMI) and FOXC2 mRNA in either adipose or muscle. There was a strong inverse relation between adipose FOXC2 mRNA and insulin sensitivity, using the frequently sampled intravenous glucose tolerance test ( r = −0.78, P < 0.001). However, there was no relationship between muscle FOXC2 and any measure of insulin sensitivity. To separate insulin resistance from obesity, we examined FOXC2 expression in pairs of subjects who were matched for BMI but who were discordant for insulin sensitivity. Compared with insulin-sensitive subjects, insulin-resistant subjects had threefold higher levels of adipose FOXC2 mRNA ( P = 0.03). In contrast, muscle FOXC2 mRNA expression was no different between insulin-resistant and insulin-sensitive subjects. There was no association of adipose or muscle FOXC2 mRNA with either circulating or adipose-secreted TNF-α, IL-6, leptin, adiponectin, or non-esterified fatty acids. Thus adipose FOXC2 is more highly expressed in insulin-resistant subjects, and this effect is independent of obesity. This association between FOXC2 and insulin resistance may be related to the role of FOXC2 in PKA signaling.

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Loss of PDGF-B activity increases hepatic vascular permeability and enhances insulin sensitivity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00241.2011 ◽

2011 ◽

Vol 301 (3) ◽

pp. E517-E526 ◽

Cited By ~ 27

Author(s):

Summer M. Raines ◽

Oliver C. Richards ◽

Lindsay R. Schneider ◽

Kathryn L. Schueler ◽

Mary E. Rabaglia ◽

...

Keyword(s):

Insulin Sensitivity ◽

Insulin Signaling ◽

Insulin Action ◽

Basolateral Membrane ◽

Tolerance Test ◽

Whole Body ◽

Glucose Disposal ◽

Permeability Barrier ◽

Loss Of Function ◽

Transendothelial Transport

Hepatic vasculature is not thought to pose a permeability barrier for diffusion of macromolecules from the bloodstream to hepatocytes. In contrast, in extrahepatic tissues, the microvasculature is critically important for insulin action, because transport of insulin across the endothelial cell layer is rate limiting for insulin-stimulated glucose disposal. However, very little is known concerning the role in this process of pericytes, the mural cells lining the basolateral membrane of endothelial cells. PDGF-B is a growth factor involved in the recruitment and function of pericytes. We studied insulin action in mice expressing PDGF-B lacking the proteoglycan binding domain, producing a protein with a partial loss of function (PDGF-B ret/ ret). Insulin action was assessed through measurements of insulin signaling and insulin and glucose tolerance tests. PDGF-B deficiency enhanced hepatic vascular transendothelial transport. One outcome of this change was an increase in hepatic insulin signaling. This correlated with enhanced whole body glucose homeostasis and increased insulin clearance from the circulation during an insulin tolerance test. In obese mice, PDGF-B deficiency was associated with an 80% reduction in fasting insulin and drastically reduced insulin secretion. These mice did not have significantly higher glucose levels, reflecting a dramatic increase in insulin action. Our findings show that, despite already having a high permeability, hepatic transendothelial transport can be further enhanced. To the best of our knowledge, this is the first study to connect PDGF-B-induced changes in hepatic sinusoidal transport to changes in insulin action, demonstrating a link between PDGF-B signaling and insulin sensitivity.

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An increase in plasma adiponectin multimeric complexes follows hypocaloric diet-induced weight loss in obese and overweight pre-menopausal women

Clinical Science ◽

10.1042/cs20060296 ◽

2007 ◽

Vol 112 (11) ◽

pp. 557-565 ◽

Cited By ~ 42

Author(s):

Jan Polak ◽

Zuzana Kovacova ◽

Martin Jacek ◽

Eva Klimcakova ◽

Michaela Kovacikova ◽

...

Keyword(s):

Weight Loss ◽

Insulin Sensitivity ◽

Hypocaloric Diet ◽

Whole Body ◽

Diabetic Patients ◽

Model Assessment ◽

Obese Women ◽

Type 2 Diabetic Patients ◽

Plasma Adiponectin ◽

Insulin Resistant

Adiponectin is involved in the regulation of glucose and fatty acid metabolism, influences whole-body insulin sensitivity and protects arterial walls against the development of atherosclerosis. Plasma adiponectin is decreased in obese, insulin-resistant and Type 2 diabetic patients. Adiponectin circulates in plasma as high-, medium- and low-molecular-weight (‘mass’) forms (HMW, MMW and LMW respectively). The HMW form is believed to be closely associated with insulin sensitivity. The aim of the present study was to investigate whether diet-induced changes in body weight and insulin sensitivity were associated with changes in the quantity of adiponectin multimeric complexes. A total of 20 overweight or obese women (age, 39.4±9.5 years; body mass index, 32.2±6.4 kg/m2) underwent 12 weeks of low caloric diet (600 kcal/day less than energy requirements; where 1 kcal≈4.184 kJ). Plasma samples were drawn before and after the study for biochemical analysis and Western blot detection of adiponectin multimeric complexes. The hypocaloric diet resulted in a weight reduction (89.8±16.4 kg compared with 83.1±15.6 kg; P<0.001) and an improvement in whole-body insulin sensitivity, as measured by HOMA (homoeostasis model assessment index; 1.9±0.8 compared with 1.5±0.7; P=0.013). Increases in the quantities of the HMW, MMW and LMW forms by 5.5, 8.5 and 18.1% respectively, were observed (P<0.05 for all of the forms). Total plasma adiponectin was increased by 36% with borderline significance (P=0.08). No correlations between changes in adiponectin complexes and changes in indices of insulin sensitivity were observed. In conclusion, diet-induced weight loss improved insulin sensitivity as well as increased the amount of HMW, MMW and LMW adiponectin complexes in plasma.

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Role of patatin-like phospholipase domain-containing 3 gene for hepatic lipid content and insulin resistance in diabetes

10.2337/figshare.12315737.v1 ◽

2020 ◽

Author(s):

Oana P. Zaharia ◽

Klaus Strassburger ◽

Birgit Knebel ◽

Yuliya Kupriyanova ◽

Yanislava Karusheva ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Lipid Content ◽

Whole Body ◽

Hepatic Lipid ◽

Insulin Resistant ◽

Increased Risk ◽

Glucose Tolerant ◽

Hepatic Lipid Content

<a>Objective</a>: The rs738409(G) single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene associates with increased risk and progression of nonalcoholic fatty liver disease (NAFLD). As the recently-described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (HCL) and insulin sensitivity in recent-onset diabetes mellitus. Research Design and Methods: A total of 917 participants of the German Diabetes Study underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution and magnetic resonance spectroscopy. Results: The G allele associated positively with HCL (β=0.36, p<0.01), independent of age, sex and BMI across the whole cohort, but not in the individual clusters. SIRD exhibited lowest whole-body insulin sensitivity compared to severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD) and severe autoimmune diabetes clusters (SAID; all p<0.001). Interestingly, SIRD presented with higher prevalence of the rs738409(G) SNP compared to other clusters and the glucose-tolerant control group (p<0.05). HCL was higher in SIRD [13.6 (5.8;19.1)%] compared to MOD [6.4 (2.1;12.4)%, p<0.05], MARD [3.0 (1.0;7.9)%, p<0.001], SAID [0.4 (0.0;1.5)%, p<0.001] and the glucose tolerant group [0.9 (0.4;4.9)%, p<0.001]. Although the PNPLA3 polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G allele carriers had higher circulating free fatty acid concentrations and greater adipose-tissue insulin resistance compared to non-carriers (both p<0.001). Conclusions: Members of the severe insulin resistant diabetes cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose-tissue insulin resistance and excessive lipolysis may contribute to their NAFLD.

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Abstract 17025: Myeloid Rage Protects From Insulin Resistance in Mice Fed High Fat Diet

Circulation ◽

10.1161/circ.142.suppl_3.17025 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Lakshmi Arivazhagan ◽

Henry Ruiz ◽

Robin Wilson ◽

Laura Frye ◽

Ravichandran Ramasamy ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Body Mass ◽

High Fat Diet ◽

Whole Body ◽

High Fat ◽

Double Knockout ◽

Euglycemic Clamp ◽

Insulin Resistant ◽

Hyperinsulinemic Euglycemic Clamp

Introduction: Obesity is a major global health problem, with over one third of adults in the US classified as obese. Obesity often leads to a state of insulin resistance (IR), type 2 diabetes (T2D) and its complications. We previously showed that the receptor for advanced glycation end products (RAGE) and its ligands contribute to the pathogenesis of obesity and IR, as whole body and adipocyte-specific Ager (gene encoding RAGE) deleted mice fed a high fat diet (HFD) were significantly protected from weight gain and IR. Here, we hypothesize that myeloid RAGE contributed to IR upon HFD feeding. Methods: We generated mice with myeloid-specific (MDR) LyzMCre(+/+).Ager flox/flox and adipocyte and myeloid-specific (Double Knockouts) AdipoQCre(-/+)LyzMCre(+/+).Ager flox/flox deletion of Ager and LysMCre mice were used as control. Mice were fed either standard chow (LFD) or HFD (60% kcal/fat) for 3 months starting at age 6 weeks. Mice were assessed for body mass and composition, glucose and insulin sensitivity and whole body glucose metabolism by hyperinsulinemic-euglycemic clamp studies. Results: After 3 months HFD, there were no significant differences in body mass, body composition, food intake, energy expenditure and physical activity of the MDR mice vs. controls. Similar findings were observed in mice fed LFD. However, surprisingly, in HFD-fed mice, insulin tolerance tests and hyperinsulinemic-euglycemic clamp studies showed decreased insulin sensitivity and insulin action in the MDR vs. control mice, indicating that the MDR mice were more insulin resistant. The Double Knockout (myeloid/adipocyte) Cre (+) mice were more glucose tolerant and insulin sensitive compared to MDR mice, showing that deletion of Ager in the adipocytes rescued the adverse effects of Ager deletion in myeloid cells. Conclusions: Myeloid Ager protects from IR in mice fed HFD. Furthermore, in MDR mice, concomitant adipocyte-specific deletion of Ager rescues these mice from IR and, at the same time, reduces HFD-induced adiposity. The mechanisms underlying these findings are under active investigation.

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Rac1 in Muscle Is Dispensable for Improved Insulin Action After Exercise in Mice

Endocrinology ◽

10.1210/en.2016-1220 ◽

2016 ◽

Vol 157 (8) ◽

pp. 3009-3015 ◽

Cited By ~ 7

Author(s):

Lykke Sylow ◽

Lisbeth L. V. Møller ◽

Gommaar D'Hulst ◽

Peter Schjerling ◽

Thomas E. Jensen ◽

...

Keyword(s):

Insulin Sensitivity ◽

Insulin Action ◽

Tolerance Test ◽

Whole Body ◽

Wild Type ◽

Acute Bout ◽

Insulin Resistant ◽

Insulin Tolerance ◽

Rac1 Activity ◽

Sensitizing Effect

Exercise has a potent insulin-sensitivity enhancing effect on skeletal muscle, but the intracellular mechanisms that mediate this effect are not well understood. In muscle, Ras-related C3 botulinum toxin substrate 1 (Rac1) regulates both insulin- and contraction-stimulated glucose transport and is dysregulated in insulin resistant muscle. However, whether Rac1 is involved in mediating enhanced insulin sensitivity after an acute bout of exercise is unresolved. To address this question, we investigated after exercise whole-body (insulin tolerance test) as well as muscle (insulin-stimulated 2-deoxyglucose transport in isolated soleus muscle) insulin sensitivity in inducible muscle-specific Rac1 knockout (mKO) and wild-type (WT) littermate mice. Previous exercise enhanced whole-body insulin sensitivity by 40% in WT mice and rescued the insulin intolerance in Rac1 mKO mice by improving whole-body insulin sensitivity by 230%. In agreement, previous exercise significantly improved insulin sensitivity by 20% in WT and by 40% in Rac1 mKO soleus muscles. These findings suggest that muscle Rac1 is dispensable for the insulin sensitizing effect of exercise. Moreover, insulin resistance in Rac1 mKO mice can be completely normalized by previous exercise explaining why insulin resistant patients can increase insulin action with exercise despite dysfunctional Rac1 activity in muscle.

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