Attenuation of Hepatic Leptin Signalling Leads to Improved Glucose Tolerance.

      The hormone leptin plays a crucial role in the maintenance of body weight and lipid and glucose metabolism. The dramatic impact of leptin on metabolism is highlighted by the fact that leptin administration to leptin-deficient ob/ob mice acutely lowers plasma glucose prior to any change in body mass. In addition to the well-defined effects of leptin on the hypothalamus, leptin also acts at peripheral sites including the liver. Consistent with this, we and others have demonstrated that leptin has direct effects on cultured hepatocytes. Further, leptin treatment of leptin deficient ob/ob and lipodystrophic mice reduces liver triglyceride levels and improves hepatic insulin sensitivity. To further delineate the mechanisms by which leptin regulates body composition, lipid and glucose metabolism, we generated mice in which leptin signalling is attenuated in hepatocytes. The lack of hepatic leptin signalling did not impact weight gain or body composition. Interestingly, despite a great deal of evidence that leptin promotes lipid oxidation in tissues, the absence of hepatic leptin signalling did not increase liver cholesterol or triglyceride levels in year old mice. Also, loss of leptin signalling in the liver did not affect fasting triglyceride, cholesterol, or free fatty acid levels in 6 and 12 week old mice. Further, fasting and midnight randomfed blood glucose levels were unchanged in 6, 12, and 16 week old mice lacking hepatic leptin signalling. Surprisingly, the loss of hepatic leptin signalling did lead to an improvement in glucose tolerance in male mice on chow as well as a high-fat diet. Further, hyperinsulinemic-euglycemic clamp studies revealed an improvement in hepatic insulin sensitivity in relation to littermate controls. Collectively these data reveal that leptin action on the liver can influence lipid and glucose metabolism and that leptin sensitivity in the liver may contribute to aspects of type 2 diabetes.
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