Disruption of Hepatic Leptin Signaling Protects Mice From Age- and Diet-Related Glucose Intolerance

Abstract

OBJECTIVEThe liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver.RESEARCH DESIGN AND METHODSTo explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals.RESULTSThe loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver.CONCLUSIONSThese data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver.

A Role for Hepatic Leptin Signaling in Lipid Metabolism via Altered Very Low Density Lipoprotein Composition and Liver Lipase Activity in Mice

“…1A), but the accumulation in plasma triglycerides occurred at similar rates in Lepr flox/flox AlbCreþ mice and their Lepr flox/flox AlbCreÀ littermate controls. Because insulin suppresses VLDL triglyceride secretion 17 and the livers of Lepr flox/flox AlbCreþ mice are more sensitive to the effects of insulin, 13 we examined whether a bolus of insulin could differentially affect VLDL triglyceride secretion in these mice. In response to insulin, there was a decreased rate of plasma triglyceride accumulation in both Lepr flox/flox AlbCreþ mice and littermate controls (Figs.…”

“…We also generated mice with a loss of hepatic leptin signaling wherein the leptin signaling domain is removed specifically from hepatocytes. 13 These mice were protected from age-and diet-related glucose intolerance and had increased hepatic insulin sensitivity. 13 Further, these mice had elevated liver triglyceride and cholesterol levels, 13 indicating an alteration in hepatic lipid metabolism.…”

“…13 These mice were protected from age-and diet-related glucose intolerance and had increased hepatic insulin sensitivity. 13 Further, these mice had elevated liver triglyceride and cholesterol levels, 13 indicating an alteration in hepatic lipid metabolism. We have now discovered that mice lacking hepatic leptin signaling have larger apolipoprotein B (apoB)-containing lipoproteins and elevated triglyceride levels in very low density lipoprotein (VLDL) particles.…”

“…6,8,12 Furthermore, leptin treatment in ob/ob mice can reverse hepatic steatosis, 7 potentially due to direct effects of leptin on the liver. 13,14 To address the direct effects of leptin on the liver, Cohen et al 15 knocked out leptin receptors specifically in hepatocytes. Surprisingly, they found no accumulation of hepatic lipids, but other aspects of lipid metabolism were not explored.…”

Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

“…Hyperinsulinemic-euglycemic clamps were performed as previously described (32)(33)(34). Mice were fasted overnight and anesthetized with acepromazine, midazolam, and fentanyl, with an initial dose by intraperitoneal injection and top-up doses by subcutaneous injection.…”