The hormone leptin plays a crucial role in maintenance of body weight and glucose homeostasis. This occurs through central and peripheral pathways, including regulation of insulin secretion by pancreatic beta cells. To study this further in mice, we disrupted the signaling domain of the leptin receptor gene in beta cells and hypothalamus. These mice develop obesity, fasting hyperinsulinemia, impaired glucose-stimulated insulin release, and glucose intolerance, similar to leptin receptor null mice. However, whereas complete loss of leptin function causes increased food intake, this tissue-specific attenuation of leptin signaling does not alter food intake or satiety responses to leptin. Moreover, unlike other obese models, these mice have reduced fasting blood glucose. These results indicate that leptin regulation of glucose homeostasis extends beyond insulin sensitivity to influence beta cell function, independent of pathways controlling food intake. These data suggest that defects in this adipoinsular axis could contribute to diabetes associated with obesity.

Objective-Scavenger receptor class B type I (SR-BI) is a cell-surface HDL receptor that is implicated in reverse cholesterol transport and protection against atherosclerosis. We have previously demonstrated that SR-BI/apolipoprotein E double-knockout mice develop severe occlusive coronary artery disease and myocardial infarction and die at Ϸ6 weeks of age. To determine if this is a general effect of a lack of SR-BI, we generated mice deficient in both SR-BI and the LDL receptor. Methods and Results-Complete ablation of SR-BI expression in LDL receptor knockout mice resulted in increased plasma cholesterol associated with HDL particles of abnormally large size and a 6-fold increase in diet-induced aortic atherosclerosis but no macroscopic evidence of early-onset coronary artery disease, cardiac pathology, or early death. Furthermore, selective elimination of SR-BI expression in bone marrow-derived cells resulted in increased diet-induced atherosclerosis in LDL receptor knockout mice without concomitant alterations in the distributions of plasma lipoprotein cholesterol. 1 The ability of HDL to protect against atherosclerosis 2 may involve several mechanisms, eg, protecting LDL from oxidation and efficient scavenger receptor-mediated uptake 3 and regulating endothelial cell metabolism (eg, controlling endothelial NO synthase activity via scavenger receptor class B type I [SR-BI] 4,5 ). HDL also mediates reverse cholesterol transport (RCT) 6,7 in which cholesterol is transferred from macrophage foam cells to HDL (efflux), esterified, delivered to liver (directly from HDL or indirectly after transfer to other lipoproteins), and subsequently recycled or secreted in bile. Hepatic (and steroidogenic cell) uptake of cholesteryl esters directly from HDL involves selective lipid uptake, the net transfer of mainly neutral lipids of HDL without net uptake and degradation of its apolipoproteins. 8 Conclusions-SR-BI See page 1486SR-BI mediates physiologically relevant selective HDL lipid uptake. 9 -14 Hepatic SR-BI overexpression in mice drastically reduces plasma HDL cholesterol and increases biliary cholesterol levels. 10 -12 Conversely, complete elimination of SR-BI in mice (null mutant) increases plasma HDL cholesterol in abnormally large HDL particles, decreases biliary cholesterol levels, and reduces lipid stores in steroidogenic tissues. 14 -16 Mice with partially reduced SR-BI attributable to a promoter insertion (SR-BIatt mouse) exhibit phenotypes similar to those of heterozygous null mutants (hepatic SR-BI expression Ϸ50% of control 13,14 ). Analysis of these mice confirmed and extended conclusions drawn from the heterozygous and homozygous null SR-BI knockout (KO) mice. 13,14,17,18 SR-BI can also mediate efflux of unesterified cholesterol to HDL in cultured cells 19 ; however, the physiological significance of this activity is unclear.The critical role of SR-BI in HDL metabolism suggested that SR-BI expression levels might influence development of atherosclerosis. We and others have examined the effects of loss o...

OBJECTIVELeptin therapy has been found to reverse hyperglycemia and prevent mortality in several rodent models of type 1 diabetes. Yet the mechanism of leptin-mediated reversal of hyperglycemia has not been fully defined. The liver is a key organ regulating glucose metabolism and is also a target of leptin action. Thus we hypothesized that exogenous leptin administered to mice with streptozotocin (STZ)-induced diabetes reverses hyperglycemia through direct action on hepatocytes.RESEARCH DESIGN AND METHODSAfter the induction of diabetes in mice with a high dose of STZ, recombinant mouse leptin was delivered at a supraphysiological dose for 14 days by an osmotic pump implant. We characterized the effect of leptin administration in C57Bl/6J mice with STZ-induced diabetes and then examined whether leptin therapy could reverse STZ-induced hyperglycemia in mice in which hepatic leptin signaling was specifically disrupted.RESULTSHyperleptinemia reversed hyperglycemia and hyperketonemia in diabetic C57Bl/6J mice and dramatically improved glucose tolerance. These effects were associated with reduced plasma glucagon and growth hormone levels and dramatically enhanced insulin sensitivity, without changes in glucose uptake by skeletal muscle. Leptin therapy also ameliorated STZ-induced hyperglycemia and hyperketonemia in mice with disrupted hepatic leptin signaling to a similar extent as observed in wild-type littermates with STZ-induced diabetes.CONCLUSIONSThese observations reveal that hyperleptinemia reverses the symptoms of STZ-induced diabetes in mice and that this action does not require direct leptin signaling in the liver.

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.