). Here we examine whether intracerebroventricular (ICV) leptin administration regulates peripheral and hepatic insulin action. Recombinant mouse leptin (n ‫؍‬ 14; 0.02 or 1 g/kg⅐h) or vehicle (n ‫؍‬ 9) were administered ICV for 6 h to conscious rats, and insulin action was determined by insulin (3 milliunits/kg⅐min) clamp and tracer dilution techniques. During physiologic hyperinsulinemia (ϳ65 microunits/ml), the rates of glucose uptake (R d , 20.1 ؎ 0.6 and 23.1 ؎ 0.7 versus 21.7 ؎ 0.6 mg/kg⅐min; p ‫؍‬ NS), glycolysis and glycogen synthesis were similar in rats receiving low-and high-dose leptin versus vehicle. ICV leptin resulted in a 2-3-fold increase in hepatic phosphoenolpyruvate carboxykinase mRNA levels. Glycogenolysis and PEP-gluconeogenesis (2.1 ؎ 0.3 mg/ kg⅐min) contributed similarly to endogenous glucose production (GP) in the vehicle-infused group. However, gluconeogenesis accounted for ϳ80% of GP in both groups receiving ICV leptin, while hepatic glycogenolysis was markedly suppressed (0.7 ؎ 0.3 and 1.2 ؎ 0.3 versus 2.2 ؎ 0.4 mg/kg⅐min, in rats receiving low-and high-dose leptin versus vehicle, respectively; p < 0.01). In summary, short-term ICV leptin administration: 1) failed to affect peripheral insulin action, but 2) induced a striking re-distribution of intrahepatic glucose fluxes. The latter effect largely reproduced that of leptin given systemically at much higher doses. Thus, the regulation of hepatic glucose fluxes by leptin is largely mediated via its central receptors.Leptin, the protein encoded by the ob gene, is an anorectic hormone secreted by adipose cells (1-6). The effects of leptin on food intake are reproduced by its injection directly in the central nervous system, thus suggesting a prominent role of the hypothalamic receptors in mediating its actions (7-12). In the long term, circulating leptin levels correlate with adiposity (3,8,10,13,14) and leptin has been suggested to function as a "biochemical messenger" between fat depots and the hypothalamus (7,10,11,14,15).Nutritional and hormonal factors can also regulate ob gene expression in adipose cells and leptin levels in plasma (3,13,14,16,17). Most important, it has become increasingly evident that leptin plays in turn an important role in the regulation of carbohydrate and lipid metabolism (9, 14, 18 -24). We have recently demonstrated that marked and acute elevations in the plasma leptin concentrations modulate the hepatic gene expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) 1 and the rate of gluconeogenesis (22). It is presently unknown whether the latter metabolic effects of leptin are, at least in part, mediated through its action on hypothalamic receptors.Therefore the primary aim of this study was to examine the metabolic impact of intracerebroventricular (ICV) infusions of leptin on peripheral and hepatic glucose metabolism under basal conditions and in response to physiologic hyperinsulinemia. Furthermore, as recent studies have suggested that a highly selective ␤ 3 -adrenergic recep...

Leptin, the product of the Obese (Lep) gene, orchestrates behavioral and metabolic responses to nutrient intake. Here, we demonstrate tissue-specific autoregulation of Lep. Moderate increases in circulating leptin considerably decreased Lep expression in adipose tissue and induced lep expression in skeletal muscle, a tissue that normally does not express this gene. Changes in nutrient availability resulted in rapid alterations in Lep autoregulation. These findings demonstrate negative feedback regulation of Lep in fat, and indicate that leptin secretion can function as a vehicle of 'cross-talk' between adipose tissue and skeletal muscle, leading to tissue-specific modulation of the 'leptin signal'.