Identify factors associated with preserved hepatic insulin sensitivity despite of hepatic steatosis.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE92746 | GEO | 2016/12/23
SECONDARY ACCESSION(S): PRJNA358510
REPOSITORIES: GEO
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Project description:The obese, insulin resistant state is characterized by impairments in lipid metabolism. Dietary polyphenols might improve these deteriorations. We have previously shown that 3-days supplementation of combined Epigallocatechin-gallate and Resveratrol (E+R) increased energy expenditure, which was accompanied by improved metabolic flexibility after a high-fat mixed-meal (HFMM) in men. The present study aimed to investigate whether these short-term effects translate into longer-term improvement of insulin sensitivity and lipid metabolism. In this randomized, double-blind study, 42 overweight subjects (21 male, 38±2 yrs, BMI 29.7±0.5 kg/m2, HOMA-IR 2.1±0.2) received either E+R (300 and 80 mg/d, respectively) or placebo (PLA) for 12 weeks (3 months). Before (t0) and after (t3) intervention, tissue-specific insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp with stable isotope infusion. Fasting and postprandial (HFMM) lipid metabolism was assessed using indirect calorimetry and blood sampling. Adipose tissue and skeletal muscle lipolysis was measured using microdialysis in men and skeletal muscle biopsies were collected to assess mitochondrial function and gene expression alterations via microarray analysis. E+R supplementation increased fasting (P=0.06) and postprandial (P=0.03) fat oxidation but did not alter energy expenditure compared to PLA. This was accompanied by an E+R-induced increase in oxidative capacity in permeabilized muscle fibers (p<0.05). Moreover, E+R supplementation attenuated the increase in plasma triacylglycerol concentration that was observed in the PLA group (AUC, p<0.05), and tended to decrease visceral fat mass (P=0.09). Finally, insulin-stimulated glucose disposal and suppression of endogenous glucose production were not affected by E+R supplementation. 12 weeks E+R supplementation increased whole-body fat oxidation and skeletal muscle oxidative capacity, but this did not translate into increased tissue-specific insulin sensitivity in overweight and obese subjects. To identify pathways that may underlie the E+R-induced improvement of skeletal muscle mitochondrial capacity, we performed microarray analysis on skeletal muscle biopsies (vastus lateralis muscle), collected before and after 12-weeks E+R or PLA treatment. Gene Set Enrichment Analysis (GSEA) indicated that the most upregulated pathways after E+R supplementation were related to the citric acid cycle and respiratory electron transport chain, while pathways related to carbohydrate metabolism were upregulated in the PLA group. In this randomized, double-blind placebo-controlled, parallel intervention trial, subjects received either a combination of E+R supplements (INTV, 282 mg/d and 80 mg/d, respectively) or placebo (PLA, partly hydrolyzed microcrystalline cellulose-filled capsules) for a period of 12 weeks (3 months) to assess effects of E+R supplementation on tissue-specific insulin sensitivity (primary outcomes) and fasting and postprandial substrate metabolism (secondary outcomes). Skeletal muscle (m. vastus lateralis) biopsies were taken under local anesthesia during fasting conditions before (t0) and after the 12-weeks (t3) intervention period. Extraxted RNA was hybridized on HTA 2.0 Affymetrix arrays and microarray analysis was performed on paired sample sets for 27 subjects (p, PLA n = 14; E+R n = 13).
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Project description:Hepatic lipid accumulation is a hallmark of type 2 diabetes (T2D) and associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and also knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia, and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from obese humans support that hepatic GABA production and transport are associated with serum insulin, HOMA-IR, T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.
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Project description:The obese, insulin resistant state is characterized by impairments in lipid metabolism. Dietary polyphenols might improve these deteriorations. We have previously shown that 3-days supplementation of combined Epigallocatechin-gallate and Resveratrol (E+R) increased energy expenditure, which was accompanied by improved metabolic flexibility after a high-fat mixed-meal (HFMM) in men. The present study aimed to investigate whether these short-term effects translate into longer-term improvement of insulin sensitivity and lipid metabolism. In this randomized, double-blind study, 42 overweight subjects (21 male, 38±2 yrs, BMI 29.7±0.5 kg/m2, HOMA-IR 2.1±0.2) received either E+R (300 and 80 mg/d, respectively) or placebo (PLA) for 12 weeks (3 months). Before (t0) and after (t3) intervention, tissue-specific insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp with stable isotope infusion. Fasting and postprandial (HFMM) lipid metabolism was assessed using indirect calorimetry and blood sampling. Adipose tissue and skeletal muscle lipolysis was measured using microdialysis in men and skeletal muscle biopsies were collected to assess mitochondrial function and gene expression alterations via microarray analysis. E+R supplementation increased fasting (P=0.06) and postprandial (P=0.03) fat oxidation but did not alter energy expenditure compared to PLA. This was accompanied by an E+R-induced increase in oxidative capacity in permeabilized muscle fibers (p<0.05). Moreover, E+R supplementation attenuated the increase in plasma triacylglycerol concentration that was observed in the PLA group (AUC, p<0.05), and tended to decrease visceral fat mass (P=0.09). Finally, insulin-stimulated glucose disposal and suppression of endogenous glucose production were not affected by E+R supplementation. 12 weeks E+R supplementation increased whole-body fat oxidation and skeletal muscle oxidative capacity, but this did not translate into increased tissue-specific insulin sensitivity in overweight and obese subjects. To identify pathways that may underlie the E+R-induced improvement of skeletal muscle mitochondrial capacity, we performed microarray analysis on skeletal muscle biopsies (vastus lateralis muscle), collected before and after 12-weeks E+R or PLA treatment. Gene Set Enrichment Analysis (GSEA) indicated that the most upregulated pathways after E+R supplementation were related to the citric acid cycle and respiratory electron transport chain, while pathways related to carbohydrate metabolism were upregulated in the PLA group.
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Project description:Interventions: Insulin resistance group:None Intervention;No insulin resistance group:None Intervention
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Study Design: Factorial
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2010-05-18 | E-GEOD-13936 | biostudies-arrayexpress
Project description:Background and Aims: Insulin resistance is a key factor in the pathogenesis of NAFLD. We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. Methods: Adipose tissue inflammation (macrophage and T cell content and gene expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed by a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in three groups stratified by adiposity, insulin sensitivity and intrahepatic triglyceride (IHTG) content: 1) metabolically-healthy lean (LEAN; n=14); 2) metabolically-healthy obese with normal IHTG content (OB-NL; n=28); and 3) metabolically-unhealthy obese with NAFLD (OB-NAFLD; n=28). The effect of plasma and SAAT-derived exosomes on insulin action (insulin-stimulated Akt phosphorylation) in human skeletal muscle myotubes was assessed in a subset of participants. Results: Proinflammatory macrophages, proinflammatory CD4 and CD8 T cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve (AUC) were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration AUC were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes obtained from the OB-NAFLD group impaired insulin action in myotubes. Conclusion: These results suggest SAAT-derived exosomes and PAI-1 are involved in the pathogenesis of systemic insulin resistance in people with obesity and NAFLD. ClinicalTrials.gov number: NCT02706262.
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Project description:Insulin regulation of hepatic gene expression is critical for controlling metabolism and preventing diabetes, atherosclerosis and NAFLD; yet, how insulin regulates gene expression in the spatial context of the liver lobule is largely unexplored. Here, we find that insulin regulates bile acid metabolism by segregating CYP8B1, the enzyme that catalyzes the 12α-hydroxylation of bile acids, from the other enzymes required for bile acid synthesis. When insulin signaling is disrupted, Cyp8b1 and the other bile acid synthesis genes become co-localized within the same zone, and 12α-hydroxylated bile acids, which drive atherosclerosis and NAFLD, are increased. Novel zone-specific genetic manipulations of Cyp8b1 that mimic the effects of insulin result in a more benign bile salt profile. Mechanistically, the zonal effects of insulin are not due to gradients of insulin concentration or signaling, but through insulin crosstalk with positional Wnt signals: Wnt and insulin act together to determine the complement of transcription factors active in the pericentral hepatocytes and thereby regulate Cyp8b1 zonation. Taken together, these data show that by repatterning gene expression in the liver lobule, insulin can transcriptionally regulate the outputs of a metabolic pathway. The spatial dimension of transcriptional regulation represents a novel lens with which to view the control of metabolism that may ultimately lead us to more precise therapies.
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