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Adipose tissue immunology, inflammation and exosomes in regulating insulin sensitivity in people with obesity and nonalcoholic fatty liver disease

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156906 | GEO | 2021/10/01

REPOSITORIES: GEO

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Project description:BACKGOUND: Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can have harmful consequences for the liver, especially in the context of obesity. OBJECTIVES: To determine whether chronic, low dose exposure to pharmaceuticals could have deleterious effects in livers of lean and obese mice. METHODS: Lean and ob/ob male mice (5-week-old) were treated for 4 months with a mixture of 11 drugs (acetaminophen, caffeine, carbamazepine, cotinine, diclofenac, erythromycin, ibuprofen, phenazone, roxithromycin, salicylic acid and sulfamethoxazole) provided in drinking water at a concentration of 1 mg/L (for each drug). At the end of the treatment, investigations were performed in liver and plasma. RESULTS: Some liver and plasma abnormalities were observed in ob/ob mice treated with the cocktail containing 1 mg/L of each drug. For this dosage, a gene expression analysis by microarray showed altered expression of circadian genes (e.g. Bmal1, Dbp, Cry1) in lean and obese mice. RT-qPCR analyses carried out in all groups of animals indicated that expression of 8 different circadian genes was significantly modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 100-1,000 ng/L. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were confirmed in an independent study performed in female mice. CONCLUSIONS: Chronic, low dose exposure to pharmaceuticals disturbed hepatic expression of circadian genes, especially in obese mice. Because some of the 11 drugs can be found in the drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, in particular for obese individuals exposed to these contaminants. C57BL/6J lean and ob/ob male mice (5-week-old) were treated for 4 months with a mixture of 11 drugs provided in drinking water at a concentration of 1 mg/L (for each drug). 4 groups were designed: untreated versus treated WT and ob/ob mice (n=6 mice per group).

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Adipose tissue immunology, inflammation and exosomes in regulating insulin sensitivity in people with obesity and nonalcoholic fatty liver disease

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