UBC Theses and Dissertations
The role of leptin in the regulation of glucose homeostasis Levi, Jasna
The fat derived hormone leptin plays a crucial role in the normal maintenance of body weight and energy expenditure, as well as glucose homeostasis. Low doses of exogenous leptin administered to leptin deficient ob/ob mice are able to reverse the hyperinsulinemia and hyperglycemia without altering body composition. As leptin has the ability to directly suppress insulin secretion from ß-cells, we hypothesise that in the absence of leptin signalling, unregulated insulin secretion leads to hyperinsulinemia which in turn leads to increased adipogenesis and insulin resistance, ultimately culminating in the development of type 2 diabetes in this mouse model. To test this hypothesis we induced an acute state of leptin deficiency with a PEGylated mouse leptin antagonist (PEG-MLA) to determine the hierarchy of leptin action. Metabolic analysis by indirect calorimetry showed that PEG-MLA treatment resulted in increased food intake and respiratory quotient without altering body composition or energy expenditure. These changes in energy balance were accompanied with increased fasting, and glucose stimulated insulin levels. PEG-MLA treated mice also displayed decreased whole-body insulin sensitivity, elevated endogenous hepatic glucose production (HPG), and impaired insulin mediated suppressed of HPG as determined by euglycemic-hyperinsulinemic clamps. Overall, these findings demonstrate that leptin signalling is important in regulating insulin secretion, and that changes in insulin sensitivity occur prior to changes in body composition and energy expenditure in a state of acute leptin deficiency. It has been recently shown that the liver derived, leptin regulated insulin-like growth factor binding protein-2 (IGFBP-2) is responsible for the anti-diabetic effect of leptin in ob/ob mice. We investigated the mechanism by which leptin regulates IGFBP-2 levels. ob/ob mice with attenuated hepatic leptin signalling or a subdiaphragmatic vagotomy were utilized to determine if leptin acts directly on the liver or centrally to increase plasma IGFBP-2. Our results show that while leptin is able to increase plasma IGFBP-2 levels in ob/ob mice in a dose dependent manner, the mechanism does not involve heptic leptin signalling or vegal efferents and remains to be elucidated.
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