Muscle-Fat Communication and Metabolic Impact

University Of California San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Obesity and diabetes are increasingly significant health care concerns. Type 2 diabetes (T2D), characterized by target tissue resistance to insulin and impaired pancreatic b-cell insulin secretion, affects 5-10% of the adult population. The amount of adipose tissue is highly correlated with and may contribute to insulin resistance. Obesity affects over 20% of the population and more than 80% of type 2 diabetics are obese, suggesting that obesity may be of pathophysiological importance to subjects genetically prone to develop diabetes. Multiple lines of evidence have suggested an endocrine role of adipose tissue to modulate energy homeostasis and insulin sensitivity, other studies suggest the possibility of a dynamic "cross-talk" relationship between muscle and fat. As skeletal muscle is the principal tissue of insulin mediated glucose disposal and the major site of peripheral insulin resistance in type 2 diabetics, these data give rise to the hypothesis that adipocyte endocrine dysfunction can result in glucose intolerance and insulin resistance in skeletal muscle. The long-term goal of this proposed study is to understand the communication between fat and muscle tissue in T2D. This study aims to determine 1) if fat from diabetic subjects contributes to the development of insulin resistance in skeletal muscle, and 2) if metabolic disturbances present in skeletal muscle from diabetic subjects alters the metabolic behavior of adipose tissue. Specifically we will use adipose and skeletal muscle biopsy tissue and cultured cells from diabetic and control subjects to ask: 1) what is the metabolic behavior of isolated adipocytes or myocytes in culture and how is it altered when their physiologic proximity is restored in culture? 2) What is the effect of T2D on the metabolic behavior of these tissues and is fat-muscle communication altered when proximity is re-established in culture? 3) Can treatment of either tissue alone with anti-diabetic thiazolidinediones alter the nature of the communication between these tissues when their physiologic relationship is restored in culture? Studying fat-muscle communication will enhance our understanding of the molecular mechanisms underlying obesity-diabetes syndromes, and may suggest new treatment strategies.