Regulation of glucose and lipid metabolism by hepatic leptin signalling

Incidences of obesity and type 2 diabetes have risen worldwide at alarming rates. While there is an undeniable correlation between obesity and type 2 diabetes, a clear mechanistic link between these two conditions has not been fully elucidated. The adipocyte-derived hormone leptin may play a role linking obesity and type 2 diabetes. Leptin can regulate body weight through its effects on the brain to decrease food intake and increase energy expenditure, but these effects are disrupted in obesity. Interestingly, leptin also has effects on glucose and lipid metabolism independent of its effects on body weight, so it is possible that disrupted leptin signalling during obesity can also perturb glucose and lipid metabolism, leading to symptoms associated with type 2 diabetes. Since the liver plays a critical role in integrating and controlling glucose and lipid metabolism, it was hypothesized that leptin resistance in the liver could play a role in the development of diabetic symptoms. To investigate this hypothesis, three complementary mouse models were used to help identify the role of leptin signalling specifically in the liver. It was found that in lean mice, hepatic leptin resistance results in increased insulin sensitivity in the liver, leading to reduced hepatic glucose output but also increased lipid accumulation and secretion of larger, more triglyceride-rich very low density lipoprotein (VLDL) particles without an increase in total plasma triglycerides. In obese, hyperinsulinemic mice lacking hepatic leptin signalling, the effects of lost leptin signalling on triglyceride metabolism were exacerbated, resulting in decreased triglyceride clearance and elevated plasma triglycerides compared to controls. These effects on plasma triglycerides were reversed when hepatic leptin signalling was restored in a mouse model of total leptin resistance. Collectively, these data reveal a possible role for hepatic leptin resistance in the development of diabetic symptoms during obesity.Medicine, Faculty ofCellular and Physiological Sciences, Department ofGraduat