Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men

2010 ◽  
Vol 299 (5) ◽  
pp. E752-E763 ◽  
Author(s):  
A. C. Alibegovic ◽  
M. P. Sonne ◽  
L. Højbjerre ◽  
J. Bork-Jensen ◽  
S. Jacobsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Dna Methylation ◽  
Er Stress ◽  
Mitochondrial Function ◽  
Physical Inactivity ◽  
Young Men ◽  
Bed Rest ◽  
Peroxisome Proliferator ◽  
Gene Expressions ◽  
Expression Of Genes

Physical inactivity is a risk factor for insulin resistance. We examined the effect of 9 days of bed rest on basal and insulin-stimulated expression of genes potentially involved in insulin action by applying hypothesis-generating microarray in parallel with candidate gene real-time PCR approaches in 20 healthy young men. Furthermore, we investigated whether bed rest affected DNA methylation in the promoter region of the peroxisome proliferator-activated receptor-γ coactivator-1α ( PPARGC1A) gene. Subjects were reexamined after 4 wk of retraining. We found that bed rest induced insulin resistance and altered the expression of more than 4,500 genes. These changes were only partly normalized after 4 wk of retraining. Pathway analyses revealed significant downregulation of 34 pathways, predominantly those of genes associated with mitochondrial function, including PPARGC1A. Despite induction of insulin resistance, bed rest resulted in a paradoxically increased response to acute insulin stimulation in the general expression of genes, particularly those involved in inflammation and endoplasmatic reticulum (ER) stress. Furthermore, bed rest changed gene expressions of several insulin resistance and diabetes candidate genes. We also observed a trend toward increased PPARGC1A DNA methylation after bed rest. We conclude that impaired expression of PPARGC1A and other genes involved in mitochondrial function as well as a paradoxically increased response to insulin of genes involved in inflammation and ER stress may contribute to the development of insulin resistance induced by bed rest. Lack of complete normalization of changes after 4 wk of retraining underscores the importance of maintaining a minimum of daily physical activity.

scholarly journals Treatment with Lobeglitazone Attenuates Hepatic Steatosis in Diet-Induced Obese Mice

PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Sorim Choung ◽  
Kyong Hye Joung ◽  
Bo Ram You ◽  
Sang Ki Park ◽  
Hyun Jin Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Plasma Cholesterol ◽  
Cholesterol Biosynthesis ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Expression ◽  
Expression Of Genes

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. The peroxisome proliferator-activated receptor (PPAR) activators, thiazolidinediones, (TZDs), are insulin sensitizers used as a treatment for NAFLD. However, TZDs are a controversial treatment for NAFLD because of conflicting results regarding hepatic steatosis and fibrosis. To evaluate a possible effective drug for treatment of NAFLD, we investigated the effects of a newly developed TZD, lobeglitazone, with an emphasis on hepatic lipid metabolism. Lobeglitazone treatment for 4 weeks in high fat diet- (HFD-) induced obese mice (HL group) improved insulin resistance and glucose intolerance compared to HFD-induced obese mice (HU group). The gene levels related to hepatic gluconeogenesis also decreased after treatment by lobeglitazone. The livers of mice in the HL group showed histologically reduced lipid accumulation, with lowered total plasma cholesterol and triglyceride levels. In addition, the HL group significantly decreased the hepatic expression of genes associated with lipid synthesis, cholesterol biosynthesis, and lipid droplet development and increased the hepatic expression of genes associated with fatty acid β-oxidation, thus suggesting that lobeglitazone decreased hepatic steatosis and reversed hepatic lipid dysregulation. Livers with steatohepatitis contained increased levels of PPARγ and phosphorylated PPARγ at serine 273, leading to downregulation of expression of genes associated with insulin sensitivity. Notably, the treatment of lobeglitazone increased the protein levels of PPARα and diminished levels of PPARγ phosphorylated at serine 273, which were increased by a HFD, suggesting that induction of PPARα and posttranslational modification of PPARγ in livers by lobeglitazone might be an underlying mechanism of the improvement seen in NAFLD. Taken together, our data showed that lobeglitazone might be an effective treatment for NAFLD.

Fenofibrate Ameliorates Insulin Resistance of Lipoprotein Lipase Knockout Heterozygous Mice

2020 ◽  
Author(s):  
Yangxue Li ◽  
Tingting Han ◽  
Shuang Zheng ◽  
Xingxing Ren ◽  
Yaomin Hu
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Endoplasmic Reticulum ◽  
Glucose Tolerance ◽  
Er Stress ◽  
Lipid Profile ◽  
Lipoprotein Lipase ◽  
Peroxisome Proliferator ◽  
Phosphorylated Akt

Abstract Background The benefits of fenofibrate (FB), a peroxisome proliferator-activated receptor-a agonist, against hyperlipidemia have been established. We investigated the effect of fenofibrate on insulin resistance of lipoprotein lipase knockout heterozygous (LPL+/-) mice, which represent inherited hypertriglyceridemia and impaired glucose tolerance. Methods Male LPL+/- mice were treated with FB (50 mg/kg, once daily) via gavage for 8 weeks. Plasma lipid, glucose tolerance test, systemic insulin sensitivity, insulin signaling of tissues, genes and proteins related to endoplasmic reticulum (ER) stress and oxidative stress were analyzed. Results Body weight of 40-week LPL+/- with FB were reduced by 30.3% (P<0.05), while the differences of 16- and 28-week LPL+/- with FB were not significant (P>0.05). FB improved the lipid profile of both 28 and 40-week LPL+/- (P<0.001 for both), while that of 16-week LPL+/- mice with FB was unaltered (P>0.05). Glucose tolerance of 40-week LPL+/- were improved by FB (P<0.05), while that of 16- and 28-week LPL+/- with FB kept unaltered (P>0.05). Fasting insulin of 40-week LPL +/- were improved by FB (P<0.05), thus HOMA-IR of 40-week LPL+/- was declined (P<0.05). HOMA-IR of 16- and 28-week LPL+/- with FB had no change. Insulin-stimulated phosphorylated Akt (Ser473) in liver and skeletal muscle of 28-week LPL+/- was enhanced by FB (P < 0.001 and P<0.05 respectively). ER stress biomarkers were detected decreased in liver of 16- to 40-week LPL+/- with FB whereas that in muscle of LPL+/- with FB unchanged. Reduced reactive oxygen species (ROS) levels and augmented mRNA expression of superoxide dismutase (SOD) and catalase (CAT) in skeletal muscle of 28- and 40-week LPL+/- mice with FB were observed. There was no significance on ROS levels and mRNA of SOD and CAT in liver between LPL+/- mice with and without FB. Conclusions Fenofibrate improved lipid profile, glucose tolerance, systemic and tissue-specific insulin resistance of LPL knockout heterozygous mice. This may be associated with alleviated endoplasmic reticulum stress in liver and reduced oxidative stress in muscle.

scholarly journals DNA Methylation of Steroidogenic Enzymes in Benign Adrenocortical Tumors: New Insights in Aldosterone-Producing Adenomas

2020 ◽  
Vol 105 (12) ◽  
pp. e4605-e4615
Author(s):  
Guido Di Dalmazi ◽  
Luca Morandi ◽  
Beatrice Rubin ◽  
Catia Pilon ◽  
Sofia Asioli ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Outcome Measure ◽  
Cushing Syndrome ◽  
Steroidogenic Enzymes ◽  
Gene Expressions ◽  
Main Outcome Measure ◽  
Adrenocortical Tumors ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Fresh Frozen

Abstract Context DNA methylation has been identified among putative regulatory mechanisms for CYP11B2 expression in primary aldosteronism. Objective The objective of this work is to investigate DNA methylation and expression of genes encoding steroidogenic enzymes in benign adrenocortical tumors. Design and Setting This cross-sectional study took place at university hospitals. Patients We collected fresh-frozen tissues from patients with benign adrenocortical adenomas (n = 48) (nonfunctioning n = 9, autonomous cortisol secretion n = 9, Cushing syndrome n = 17, aldosterone-producing [APA] n = 13) and adrenal cortex adjacent to APA (n = 12). We collected formalin-fixed, paraffin-embedded (FFPE) specimens of paired APA and concurrent aldosterone-producing cell clusters (APCCs) (n = 6). Intervention DNA methylation levels were evaluated by quantitative bisulfite next-generation sequencing in fresh-frozen tissues (CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, HSD3B1, HSD3B2, NR5A1, STAR, and TSPO) and FFPE APA/APCC paired samples (CYP11B2). CYP11B1, CYP11B2, CYP17, CYP21, and STAR gene expressions were examined by quantitative real-time polymerase chain reaction. Main Outcome Measure The main outcome measure was DNA methylation. Results CYP11B2 methylation levels were significantly lower in APA than in other adrenal tissues (P &lt; .001). Methylation levels of the remaining genes were comparable among groups. Overall, CYP11B2 expression and DNA methylation were negatively correlated (ρ = –0.379; P = .003). In FFPE-paired APA/APCC samples, CYP11B2 methylation level was significantly lower in APA than in concurrent APCCs (P = .028). Conclusions DNA methylation plays a regulatory role for CYP11B2 expression and may contribute to aldosterone hypersecretion in APA. Lower CYP11B2 methylation levels in APA than in APCCs may suggest an APCC-to-APA switch via progressive CYP11B2 demethylation. Conversely, DNA methylation seems not to be relevant in regulating the expression of genes encoding steroidogenic enzymes other than CYP11B2.

scholarly journals Insulin resistance in obese adolescents affects the expression of genes associated with immune response

2019 ◽  
Vol 53 (2) ◽  
pp. 71-82 ◽  
Author(s):  
Dmytro O. Minchenko
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Immune Response ◽  
Expression Level ◽  
Control Group ◽  
Gene Expressions ◽  
Down Regulation ◽  
Metabolic Complications ◽  
Obese Adolescents ◽  
Expression Of Genes

AbstractObjective. The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes through changes in the expression of numerous regulatory genes.Methods. The expression level of HLA-DRA, HLA-DRB1, HLA-G, HLA-F, and NFX1 genes as well as miR-190b was measured in the blood of obese adolescents without signs of resistance to insulin and with insulin resistance in comparison with the group of relative healthy control individuals without signs of obesity.Results. It was shown that obesity without signs of insulin resistance is associated with upregulation of the expression level of HLA-DRA and HLA-DRB1 genes, but with down-regulation of HLA-G gene expression in the blood as compared to control group of relative healthy adolescents. At the same time, no significant changes were observed in the expression level of HLA-F and NFX1 genes in the blood of this group of obese adolescents. Development of insulin resistance in obese individuals leads to significant down-regulation of HLA-DRA, HLA-DRB1, HLA-G, and HLA-F gene expressions as well as to up-regulation of NFX1 gene as well as microRNA miR-190b in the blood as compared to obese patients without signs of insulin resistance.Conclusions. Results of this study provide evidence that obesity affects the expression of the subset of genes related to immune response in the blood and that development of insulin resistance in obese adolescents is associated with strong down-regulation of the expressions of HLA-DRA, HLA-DRB1, HLA-F, and HLA-G genes, which may be contribute to the development of obesity complications. It is possible that transcription factor NFX1 and miR-190b participate in downregulation of HLA-DRA gene expression in the blood of obese adolescents with insulin resistance.

Metabolic disruptions induced by reduced ambulatory activity in free-living humans

2011 ◽  
Vol 111 (4) ◽  
pp. 1218-1224 ◽  
Author(s):  
John P. Thyfault ◽  
Rikke Krogh-Madsen
Keyword(s):  
Insulin Resistance ◽  
Physical Inactivity ◽  
Direct Evidence ◽  
Bed Rest ◽  
Endurance Athletes ◽  
Central Adiposity ◽  
Ambulatory Activity ◽  
Free Living ◽  
Metabolic Outcomes ◽  
Acute Responses

Physical inactivity likely plays a role in the development of insulin resistance and obesity; however, direct evidence is minimal and mechanisms of action remain unknown. Studying metabolic outcomes that occur after transitioning from higher to lower levels of physical activity is the best tool to answer these questions. Previous studies have successfully used more extreme models of inactivity, including bed rest, or the cessation of exercise in highly trained endurance athletes, to provide novel findings. However, these models do not accurately reflect the type of inactivity experienced by a large majority of the population. Recent studies have used a more applicable model in which active (∼10,000 steps/day), healthy young controls are asked to transition to an inactive lifestyle (∼1,500 steps/day) for a 14-day period. The transition to inactivity resulted in reduced insulin sensitivity and increased central adiposity. This review will discuss the outcomes of these studies, their implications for the cause/effect relationship between central adiposity and insulin resistance, and provide rationale for why inactivity induces these factors. In addition, the experimental challenges of directly linking acute responses to inactivity to chronic disease will also be discussed.

scholarly journals The Roots ofAtractylodes macrocephalaKoidzumi Enhanced Glucose and Lipid Metabolism in C2C12 Myotubes via Mitochondrial Regulation

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Mi Young Song ◽  
Seok Yong Kang ◽  
Tae Woo Oh ◽  
Rethineswaran Vinoth Kumar ◽  
Hyo Won Jung ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Mitochondrial Function ◽  
Weight Control ◽  
Glucose Consumption ◽  
C2c12 Myotubes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Respiratory Factor ◽  
Glucose And Lipid Metabolism

The root ofAtractylodes macrocephalaKoidzumi (Atractylodis Rhizoma Alba, ARA) is a Traditional Korean Medicine and has been commonly used for weight control. Mitochondrial dysfunction appears to be a key contributor to insulin resistance, and therefore mitochondrial targeting drugs represent an important potential strategy for the treatment of insulin resistance and obesity. In this study, the authors investigated the regulatory effects of ARA on mitochondrial function with respect to the stimulation of glucose and lipid metabolism in C2C12 myotubes. After differentiating C2C12 myotubes, cells were treated with or without different concentrations (0.2, 0.5, and 1.0 mg/mL) of ARA extract. ARA extract significantly increased the expression of peroxisome proliferator-activated receptor coactivator 1 alpha (PGC1α) and the downregulations of its targets, nuclear respiratory factor-1 (NRF-1), transcription factor A (TFAM), and total ATP content in C2C12 myotubes. ARA extract also increased the expressions of PGC1αactivator and of the metabolic sensors, AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase and sirtuin (SIRT) 1. Furthermore, it significantly increased glucose uptake by enhancing glucose consumption and subsequently decreased FFA contents and increased carnitine palmitoyltransferase (CPT) 1b expression. Our study indicates that ARA has a potential for stimulating mitochondrial function and energy metabolism in muscle.

Abstract 70: PPARdelta Agonist GW1516 Attenuates Diet-Induced Dyslipidemia, Insulin Resistance and Aortic Inflammation in Ldlr -/- Mice

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Lazar Bojic ◽  
Dawn Telford ◽  
Brian Sutherland ◽  
Cynthia Sawyez ◽  
Jane Edwards ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Er Stress ◽  
Proinflammatory Cytokines ◽  
Map Kinases ◽  
Fasting Blood Glucose ◽  
M2 Macrophage ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Arginase 1

Objective: The peroxisome proliferator-activated receptor (PPAR) delta has been implicated in systemic lipid homeostasis and inflammation. However, the role of PPARdelta agonists as anti-atherogenic agents remains unclear. In the present study, we used low-density lipoprotein receptor-null mice (Ldlr-/-) fed a high fat (HF) diet to test the hypothesis that a selective PPARdelta agonist corrects metabolic dysregulation and attenuates inflammation associated with atherosclerosis. Methods and Results: Ldlr -/- mice were fed chow or HF (42% fat, 0.2% cholesterol) for 4 weeks. Subsequently, the HF group was fed either HF or HF plus GW1516 (3mg/kg/d) for a further 8 weeks. Fasting plasma triglyceride, total cholesterol and free fatty acids were significantly decreased (-50%) by intervention with GW1516. In addition, GW1516 normalized fasting blood glucose and improved glucose and insulin tolerance. GW1516 also enhanced total energy expenditure compared to HF-fed mice. In the aorta, ER-stress markers CHOP and GRP78 were significantly elevated in HF-fed mice, which were markedly attenuated by GW1516-intervention. Aortae of HF-fed mice also showed marked elevations in the expression of proinflammatory cytokines including Ccl3, Il1beta, Icam1, Tnf, Il6 and Ccl2. Furthermore, HF-aortae, compared to chow, displayed reduced expression of the M2 macrophage marker arginase-1(Arg1). Intervention with GW1516 significantly attenuated aortic expression of all examined proinflammatory cytokines, and restored Arg1 expression. Enhanced MAPKerk signalling and decreased AKT/FoxO1 signalling are known to induce inflammatory cytokine expression in vitro. HF-feeding induced phosphorylation (p) of the MAP kinases ERK1/2 and p38 and dampened levels of pAKT and pFoxO1 in the aorta. In contrast, aortae of GW1516-treated animals displayed normalized levels of pERK1/2, p-p38, pAKT and pFoxO1. Conclusions: These studies demonstrate that PPARdelta activation ameliorates dyslipidemia and insulin resistance in HF-fed Ldlr -/- mice. Furthermore, PPARdelta activation inhibits aortic ER-stress as well as dysregulation of MAPK and AKT/FoxO1 signalling induced by HF-feeding, resulting in inhibition of the inflammatory response within the aorta.

scholarly journals Bed rest and resistive vibration exercise unveil novel links between skeletal muscle mitochondrial function and insulin resistance

Diabetologia ◽  
2017 ◽  
Vol 60 (8) ◽  
pp. 1491-1501 ◽  
Author(s):  
Helena C. Kenny ◽  
Floriane Rudwill ◽  
Laura Breen ◽  
Michele Salanova ◽  
Dieter Blottner ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Bed Rest ◽  
Vibration Exercise

scholarly journals Mitochondrial Function in Skeletal Muscle Is Normal and Unrelated to Insulin Action in Young Men Born with Low Birth Weight

2008 ◽  
Vol 93 (10) ◽  
pp. 3885-3892 ◽  
Author(s):  
Charlotte Brøns ◽  
Christine B. Jensen ◽  
Heidi Storgaard ◽  
Amra Alibegovic ◽  
Stine Jacobsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Young Men ◽  
Hepatic Insulin Resistance

Objective: Low birth weight (LBW) is an independent risk factor of insulin resistance and type 2 diabetes. Recent studies suggest that mitochondrial dysfunction and impaired expression of genes involved in oxidative phosphorylation (OXPHOS) may play a key role in the pathogenesis of insulin resistance in aging and type 2 diabetes. The aim of this study was to determine whether LBW in humans is associated with mitochondrial dysfunction in skeletal muscle. Methods: Mitochondrial capacity for ATP synthesis was assessed by 31phosphorus magnetic resonance spectroscopy in forearm and leg muscles in 20 young, lean men with LBW and 26 matched controls. On a separate day, a hyperinsulinemic euglycemic clamp with excision of muscle biopsies and dual-energy x-ray absorptiometry scanning was performed. Muscle gene expression of selected OXPHOS genes was determined by quantitative real-time PCR. Results: The LBW subjects displayed a variety of metabolic and prediabetic abnormalities, including elevated fasting blood glucose and plasma insulin levels, reduced insulin-stimulated glycolytic flux, and hepatic insulin resistance. Nevertheless, in vivo mitochondrial function was normal in LBW subjects, as was the expression of OXPHOS genes. Conclusions: These data support and expand previous findings of abnormal glucose metabolism in young men with LBW. In addition, we found that the young, healthy men with LBW exhibited hepatic insulin resistance. However, the study does not support the hypothesis that muscle mitochondrial dysfunction per se is the underlying key metabolic defect that explains or precedes whole body insulin resistance in LBW subjects at risk for developing type 2 diabetes.

scholarly journals The effect of 8 days of strict bed rest on the incretin effect in healthy volunteers

2016 ◽  
Vol 120 (6) ◽  
pp. 608-614 ◽  
Author(s):  
Signe Tellerup Nielsen ◽  
Nina Majlund Harder-Lauridsen ◽  
Fabiana Braga Benatti ◽  
Anne-Sophie Wedell-Neergaard ◽  
Mark Preben Lyngbæk ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Physical Inactivity ◽  
Insulin Response ◽  
Bed Rest ◽  
Fat Free Mass ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Intravenous Glucose ◽  
C Peptide

Bed rest and physical inactivity are the consequences of hospital admission for many patients. Physical inactivity induces changes in glucose metabolism, but its effect on the incretin effect, which is reduced in, e.g., Type 2 diabetes, is unknown. To investigate how 8 days of strict bed rest affects the incretin effect, 10 healthy nonobese male volunteers underwent 8 days of strict bed rest. Before and after the intervention, all volunteers underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the following day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide, plasma incretin hormones [glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptide (GIP)], and serum glucagon were measured serially during both the OGTT and the IVGI. The incretin effect is calculated as the relative difference between the area under the curve for the insulin response during the OGTT and that of the corresponding IVGI, respectively. Concentrations of glucose, insulin, C-peptide, and GIP measured during the OGTT were higher after the bed rest intervention (all P < 0.05), whereas there was no difference in the levels of GLP-1 and Glucagon. Bed rest led to a mean loss of 2.4 kg of fat-free mass, and induced insulin resistance evaluated by the Matsuda index, but did not affect the incretin effect ( P = 0.6). In conclusion, 8 days of bed rest induces insulin resistance, but we did not see evidence of an associated change in the incretin effect.

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