Small Extracellular Vesicles and Insulin Action

Insulin resistance is commonly associated with obesity and is a major contributor to the development of obesity-related metabolic diseases, including nonalcoholic fatty liver disease, the metabolic syndrome, and type 2 diabetes (T2D). Most persons with obesity are "metabolically unhealthy" (MUO), often defined by having insulin resistance and the metabolic syndrome. However, a subset of people with obesity are metabolically healthy (MHO) and protected from the adverse metabolic effects of excess adiposity. The mechanisms that determine the differences in metabolic health between people with MUO and MHO are not unclear. This project will examine the effects of plasma and adipose tissue small extracellular vesicles (sEVs) on multi-organ insulin action. The investigators will isolate sEVs from subcutaneous abdominal adipose tissue biopsies and blood samples obtained from human participants with MHO, MUO or who are metabolically healthy and lean (MHL) and examine the effects of these sEVs on insulin resistance in muscle, liver and fat cells in culture and on multi-organ insulin sensitivity in lean and obese mice. The investigators will also identify differences in the potential bioactive molecules, namely miRNA and bioactive lipids, that are carried by sEVs. The results from this study will help determine whether plasma or adipose tissue sEVs in people who are MHL, MHO, or MUO are involved in regulating liver, muscle and adipose tissue insulin sensitivity. These results could identify novel pathways that regulate metabolic health in people and provide the foundation for exploring the potential of sEVs as a therapeutic target to prevent and treat the metabolic complications of obesity.

• Differences in the content of microRNAs within exosomes obtained from plasma and adipose tissue [Срок оценки: Baseline only (cross-sectional comparison of metabolically healthy lean, and of people with metabolically healthy or metabolically unhealthy obesity).]
• Differences in the content of lipids within exosomes obtained from plasma and adipose tissue [Срок оценки: Baseline only (cross-sectional comparison of metabolically healthy lean, and of people with metabolically healthy or metabolically unhealthy obesity).]
• Changes in the content of microRNAs within exosomes obtained from plasma and adipose tissue [Срок оценки: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity]
• Changes in the content of lipids within exosomes obtained from plasma and adipose tissue [Срок оценки: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity]
• Insulin sensitivity [Срок оценки: Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).]
• Change in insulin sensitivity [Срок оценки: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity]
• Fat mass and fat free mass [Срок оценки: Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).]
• Change in fat mass and fat free mass [Срок оценки: Before and after 10% weight loss (~4-5 months) in people with metabolically abnormal obesity]
• Abdominal adipose tissue volumes [Срок оценки: Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).]
• Change in abdominal adipose tissue volumes [Срок оценки: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity]
• Intra-hepatic triglyceride content [Срок оценки: Baseline only (cross-sectional comparison of metabolically healthy lean, and people with metabolically healthy or metabolically unhealthy obesity).]
• Change in intra-hepatic triglyceride content [Срок оценки: Before and after ~10% weight loss (~4-5 months) in people with metabolically abnormal obesity]