Pathogenic mechanisms of obesity and its cardiometabolic complications

PROJECT SUMMARY Pediatric obesity is a major health burden affecting millions of children and adolescents as it predisposes to the development of cardio-metabolic diseases early in life, such as insulin resistance, fatty liver disease, and type 2 diabetes. Our lab has recently completed a series of studies to understand the relationship between intestinal microbial activity and human metabolism in youth. We observed that intestinal fermentation, a process through which fermentable carbohydrates are processed by intestinal bacteria, results in various biological responses to protect the human body from developing obesity and some of its metabolic complications, such as insulin resistance and ectopic fat accumulation. In particular, we observed that intestinal fermentation causes 1- a reduction of plasma free fatty acids (FFA) due to the inhibition of adipose tissue lipolysis (ATL); 2- a marked entero-endocrine response to reduce appetite, characterized by an increase in the production of peptide YY (PYY) and glucagon-like peptide1 (GLP-1) and a reduced production of ghrelin. In addition, we observed that some intestinal fermentation responses are impaired in youth with obesity and insulin resistance (OIR). In light of this evidence, the current proposal will address: 1- how adipose tissue lipolysis response to intestinal fermentation is affected by insulin resistance; 2- whether changes in ATL, observed when fermentation occurs, are also associated with a reduction of glycerol-derived neo-gluconeogenesis; 3- if physical activity may restore the entero-endocrine and adipose tissue response to intestinal fermentation in youth with insulin resistance. It is the first study to test the effect of insulin resistance on the relationship between intestinal microbial metabolic activity and human metabolism (namely adipose tissue lipolysis, gluconeogenesis, and entero-endocrine response). The results will provide fundamental insight into how insulin resistance occurring in youth with obesity affects the metabolic response to fermentable carbohydrates. In fact, despite the large body of literature showing an association between intestinal microbial fermentation and human metabolism, how and whether insulin resistance may modulate this association remains unknown.