Leptin, an adipocyte-derived hormone that directly regulates both adiposity and energy homeostasis, decreases food intake and appears to partition metabolic fuels toward utilization and away from storage. Because skeletal muscle expresses the leptin receptor and plays a major role in determining energy metabolism, we studied leptin's effects on glucose and fatty acid (FA) metabolism in isolated mouse soleus and extensor digitorum longus (EDL) muscles. One muscle from each animal served as a basal control. The contralateral muscle was treated with insulin (10 mU/ml), leptin (0.01-10 ug/ml), or insulin plus leptin, and incorporation of [
C]glucose or [14 C]oleate into CO 2 and into either glycogen or triacylglycerol (TAG) was determined. Leptin increased soleus muscle FA oxidation by 42% (P < 0.001) and decreased incorporation of FA into TAG by 35% (P < 0.01) in a dose-dependent manner. In contrast, insulin decreased soleus muscle FA oxidation by 40% (P < 0.001) and increased incorporation into TAG by 70% (P < 0.001). When both hormones were present, leptin attenuated both the antioxidative and the lipogenic effects of insulin by 50%. Less pronounced hormone effects were observed in EDL muscle. Leptin did not alter insulin-stimulated muscle glucose metabolism. These data demonstrate that leptin has direct and acute effects on skeletal muscle. Diabetes 46:1360-1363, 1997 H omozygous ob/ob mice lack functional leptin, a 16-kDa peptide hormone that is expressed and secreted by adipose tissue, and exhibit an obesity syndrome characterized by hyperphagia, hypothermia, hyperlipidemia, hyperinsulinemia, and insulin resistance (1). When administered to ob/ob mice, leptin reduces food intake and increases energy expenditure (2,3). Received for publication 28 March 1997 and accepted in revised form 7 May 1997.BSA, bovine serum albumin; EDL, extensor digitorum longus; FA, fatty acid; mKRB, modified Krebs-Ringer buffer; TAG, triacylglycerol.Both lean and obese animals treated with leptin lose fat mass but retain lean body mass (2,3). In ob/ob mice, leptin also normalizes serum concentrations of glucose, insulin, and lipids (2). The latter effects are observed at low leptin doses that do not affect body weight, suggesting that leptin's metabolic effects precede its effects on food intake and weight (2). In pair-feeding studies, leptin-injected mice lose 30-50% more weight and 50-100% more fat mass than pair-fed controls (4). Leptin treatment increases energy expenditure (2), whereas energy is conserved during food restriction (4,5). These data strongly suggest that leptin modulates energy homeostasis in part through mechanisms that are independent of food intake and that it directs metabolic fuels toward oxidation and away from storage.Skeletal muscle accounts for a large proportion of insulinstimulated glucose uptake and whole-body lipid oxidation and is the major tissue contributing to resting metabolic rate. Because each of these factors is affected by leptin in ob/ob mice (2-4) and because skeletal muscle expresses both lo...