Decreased adipose tissue oxygenation is associated with insulin resistance in people with obesity
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ABSTRACT:
PROVIDER: PRJNA641129 | ENA |
REPOSITORIES: ENA
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Project description:We evaluated the potential importance of adipose tissue (AT) oxygenation on AT biology and insulin sensitivity in people. AT oxygen partial pressure (pO2), branched chain amino acid (BCAA) catabolism and marker of inflammation were determined in three groups stratified by adiposity and insulin sensitivity: 1) metabolically-healthy lean (MHL); 2) metabolically-healthy obese (MHO); and 3) metabolically-unhealthy obese (MUO). AT pO2 progressively declined from the MHL to the MHO to the MUO group, and was positively associated with hepatic and whole-body insulin sensitivity. AT pO2 was positively associated with AT expression of genes involved in BCAA catabolism and negatively associated with plasma BCAA concentrations. Although AT pO2 was negatively associated with AT markers of inflammation, it was not associated with plasma adipokine concentrations. These results support the notion that reduced AT pO2 in people with obesity contributes to insulin resistance by decreasing AT BCAA catabolism and thereby increasing plasma BCAA concentrations.
2020-12-07 | GSE152991 | GEO
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.
2021-10-01 | GSE156906 | GEO
Project description:Obesity is associated with insulin resistance, an important risk factor of type 2 diabetes, atherogenic dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease. It has been postulated that accumulation of visceral adipose tissue (VAT) causes obesity-induced insulin resistance. The major purpose of this study was to test hypothesis that prophylactic VAT removal prevents the development of obesity-induced multi-organ (liver, skeletal muscle, adipose tissue) insulin resistance, dyslipidemia, and NAFLD. Accordingly, we surgically removed epididymal VAT from adult C57BL/6J mice and then evaluated in vivo and cellular metabolic pathways involved in glucose and lipid metabolism following feeding of chronic high-fat diet (HFD). We found that VAT removal prevented HFD-induced insulin resistance and markedly increased AKT-mediated insulin signaling in subcutaneous adipose tissue (SAT), liver, and skeletal muscle. VAT removal improved plasma lipid profiling and prevented obesity-induced NAFLD. In addition, VAT removal significantly increased circulating level of adiponectin, a key insulin-sensitizing adipokine, whereas it decreased interleukin-6, a pro-inflammatory adipokine. Data obtained from RNA-sequencing suggest that VAT removal prevents obesity-induced oxidative stress and inflammation in liver and SAT respectively. These findings demonstrate the causative role of VAT in the development of obesity and related systemic metabolic complications, such as insulin resistance, dyslipidemia, and NAFLD.
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2023-12-06 | GSE222263 | GEO
Project description:Some people with obesity are resistant to the adverse metabolic effects of excess adiposity and are considered to have “metabolically healthy obesity” (MHO). However, the mechanisms responsible for MHO are not clear. We performed comprehensive cardiometabolic profiling in 20 adults with MHO (defined by features of normal insulin sensitivity), 20 age-, sex-, and BMI-matched adults with metabolically unhealthy obesity (MUO), and 15 adults who were metabolically healthy and lean (MHL). More than 120 variables were evaluated, including body composition, beta-cell function, 24-hour plasma metabolic profile, rates of de novo lipogenesis and cholesterol synthesis, plasma adipokine concentrations, oxidative stress, plasma lipoprotein profiles, cardiovascular structure/function, skeletal muscle bioactive lipids, and both adipose tissue and skeletal muscle transcriptomics. Using dimensionality reduction approaches, measures of insulinemia and skeletal muscle ceramides were the strongest discriminators of MHO and MUO status. These data clarify the characteristics associated with preserved metabolic health in response to obesity.
2024-03-06 | GSE244120 | GEO
Project description:Some people with obesity are resistant to the adverse metabolic effects of excess adiposity and are considered to have “metabolically healthy obesity” (MHO). However, the mechanisms responsible for MHO are not clear. We performed comprehensive cardiometabolic profiling in 20 adults with MHO (defined by features of normal insulin sensitivity), 20 age-, sex-, and BMI-matched adults with metabolically unhealthy obesity (MUO), and 15 adults who were metabolically healthy and lean (MHL). More than 120 variables were evaluated, including body composition, beta-cell function, 24-hour plasma metabolic profile, rates of de novo lipogenesis and cholesterol synthesis, plasma adipokine concentrations, oxidative stress, plasma lipoprotein profiles, cardiovascular structure/function, skeletal muscle bioactive lipids, and both adipose tissue and skeletal muscle transcriptomics. Using dimensionality reduction approaches, measures of insulinemia and skeletal muscle ceramides were the strongest discriminators of MHO and MUO status. These data clarify the characteristics associated with preserved metabolic health in response to obesity.
2024-03-06 | GSE244118 | GEO
Project description:Weight loss and physical activity are the cornerstones of therapy for type 2 diabetes. However, providing an effective lifestyle intervention is difficult because of limited availability of reliable programs, patient inconvenience, and cost. A worksite setting provides a unique opportunity for lifestyle therapy because it reduces these barriers. We conducted an 8-month randomized controlled trial in persons with obesity and diabetes to determine the therapeutic effects and potential mechanisms of intensive-lifestyle-therapy (energy restriction and supervised exercise training) conducted at the worksite. Intensive-lifestyle-therapy resulted in marked (17%) weight loss, associated with beneficial changes in body composition, cardiorespiratory fitness, muscle strength, glycemic control, β-cell function and insulin sensitivity in the liver, adipose tissue, and skeletal muscle, despite a decrease in diabetes medication use. These beneficial effects were associated with changes in skeletal muscle (increased metabolite content and expression of genes involved in NAD biosynthesis, sirtuin signaling, and mitochondrial biogenesis and function), adipose tissue (decreased expression of genes involved in extracellular matrix remodeling), and a major plasma mediator of insulin resistance (decreased plasma PAI-1). These findings demonstrate that effective intensive-lifestyle-therapy can be implemented at the worksite, and has profound therapeutic, clinical, physiological, and cellular effects in people with obesity and type 2 diabetes.
2022-09-08 | GSE205891 | GEO
Project description:Adipose tissue immunology, inflammation and exosomes in regulating insulin sensitivity in people with obesity and nonalcoholic fatty liver disease
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Project description:The additional therapeutic effects of regular exercise during a dietary weight loss program in people with obesity and prediabetes are unclear. We evaluated the effect of 10% weight loss, induced within ~5 months by calorie-restriction alone (Diet-ONLY, n=8) or calorie-restriction plus multi-modal exercise training (Diet+EX, n=8), on metabolic function in people with obesity and prediabetes. Whole-body (primarily muscle) and hepatic insulin sensitivity were 2-3 fold greater in the Diet+EX than the Diet-ONLY group, and were accompanied by increased muscle expression of genes involved in mitochondrial biogenesis, energy metabolism and angiogenesis in the Diet+EX group without any change in the Diet-ONLY group. There were no differences between groups in plasma branched-chain amino acids or markers of inflammation, and both interventions caused similar changes in the gut microbiome. These results demonstrate that adding regular exercise to a diet-induced weight loss program has profound metabolic benefits in people with obesity and prediabetes.
2023-04-26 | GSE230002 | GEO
Project description:Purpose: To determine how STAT1 activity in white adipocytes affects insulin sensitivity. Methods: Adipocyte specific (ADIPOQ-Cre) STAT1 fl/fl mice (STAT1 fKO) and littermate controls (STAT1 fl/fl) were placed on 60% HFD for 18 weeks, followed by metabolic phenoptying and tissue harvest for RNA-seq Results: STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1 fKO) enhanced mitochondrial function and accelerated TCA cycle flux coupled with subcutaneous WAT hyperplasia. STAT1 fKO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon gamma (IFNg) activity enhanced insulin sensitivity in diet-induced obesity. Conclusions: Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.
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