Insulin and leptin action : roles in diabetes and obesity
Obesity is a major risk factor for insulin resistance and therefore type 2 diabetes. However, the precise mechanisms whereby obesity causes insulin resistance are complex and not completely understood. The adipocyte derived hormone leptin and the pancreatic derived hormone insulin act as satiety factors to the central nervous system, regulating long-term energy homeostasis. In addition both hormones have been shown to act in the central nervous system (CNS) to acutely regulate peripheral glucose homeostasis. Leptin and insulin have also been shown to regulate pancreatic islet function. A growing amount of evidence suggests there is considerable overlap in the pathways by which these hormones act to mediate their physiological effects. The insulin receptor substrate-2 (IRS-2) protein is a critical mediator of cellular responses to insulin, especially those associated with somatic growth and carbohydrate metabolism. It has been suggested that IRS-2 signalling pathways act as a potential point of convergence for insulin and leptin signalling. Much of our current understanding of both the cellular and molecular effects of leptin and insulin has been derived from studies of murine models of obesity and diabetes. In this thesis I have exploited three such models to generate mice with defective 1) IRS-2 function (IRS-2 KO) and leptin production (ob/ob) and 2) IRS-2 function and leptin receptor (db/db) function. I have also produced mice which lack IRS-2 and STAT-3 specifically in their P-cells and hypothalamus. As insulin resistance and leptin resistance coexist in obese subjects, it was hoped that such murine models would give some insights into the contribution of these processes to the obesity phenotype and its associated insulin resistance and type 2 diabetes. In particular it was hoped to address the hypothesis that a linear relationship exists between IRS-2 and STAT-3 in mediating the effects of insulin and leptin action, with IRS-2 being upstream of the events that lead to the phosphorylation of STAT-3. Considering either systemic or tissue-specific approaches, it was evident that insults to leptin signalling in combination with lrs-2 deletion results in additive effects upon growth, adiposity, glucose homeostasis and islet function. These additive effects would indicate that IRS-2 and STAT-3 mediate these effects by acting in separate signalling pathways, as opposed to converging upon a linear pathway. However cross talk between these parallel pathways is likely to be critical for the maintenance of insulin and leptin sensitivity in target tissues.