Leptin Directly Alters Lipid Partitioning in Skeletal Muscle

Abstract

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...

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

“…[56][57][58] As depicted in Figure 3, the earlier demonstrations that leptin can act directly on skeletal muscle, specifically via the long form of the leptin receptor (ObRb), to stimulate glucose utilization in a PI3K-dependent manner 59,60 and lipid oxidation via the activation of AMP-activated protein kinase (AMPK) leading to inhibition of ACCs 58,61 prompted us to investigate whether leptin could also exert direct control on thermogenesis in skeletal muscle. Using a method that involves repeated measurements of O 2 consumption in intact muscle perifused ex vivo with Krebs-Ringer buffer, we found that leptin could directly stimulate thermogenesis in skeletal muscle via ObRb, 62 and that this thermogenic effect of leptin, which requires PI3K activity (since it is inhibited by wortmannin), is potentiated by insulin, a potent activator of PI3K.…”

“…A requirement for AMPK activation and for entry of fatty acids through the mitochondrial b-oxidation pathway was also suggested by the fact that leptin-induced thermogenesis was inhibited either in the presence of araA (an inhibitor of AMPK) or by addition of etomoxir, an inhibitor of CPT-1. 63 In other experiments that involved interference with key control points of intermediary metabolism in order to investigate the nature of an 'apparent' link between leptin's direct effects on skeletal muscle to stimulate glucose metabolism, 58-60 lipid oxidation [57][58][59][60][61] and thermogenesis, 62 evidence emerged of a requirement for de novo lipogenesis in the mechanism by which leptin stimulates muscle thermogenesis. 63 Specifically, the direct thermogenic effect of leptin on skeletal muscle O 2 consumption was found to be completely inhibited by the addition of any one of the following compounds that would inhibit the synthesis of lipids from glucose, namely (a) 2-deoxyglucose, which interferes with glucose metabolism, (b) hydroxy-citrate, which inhibits citrate lyase and hence the conversion of citrate to acetyl-CoA and (c) cerulenin, which inhibits fatty acid synthase and hence the conversion of malonyl-CoA to fatty acids.…”

Undernutrition during suckling in rats elevates plasma adiponectin and its receptor in skeletal muscle regardless of diet composition: a protective effect?

“…11 CPT-1 mRNA expression can be affected by nutritional states, and both fasting and fat feeding increase its expression. 12 Many circulating hormones secreted by white adipose tissue (WAT) including adiponectin 13,14 and leptin 15,16 can stimulate fatty-acid oxidation and glucose uptake. Undernutrition in early life may have long-lasting effects on the regulation of these hormones.…”

Nutritional regulation of leptin in humans

“…Additionally, the importance of leptin to reproduction has been highlighted by the lack of sexual maturation in people who are genetically deficient in leptin [5] or the leptin receptor [6]. Although many of leptin's effects are centrally mediated, there is growing evidence that peripheral leptin receptors mediate leptin's proliferative effects on haemopoietic cells [7] and its anti-lipogenic effects on muscle and pancreatic islets [8,9].Because leptin has a critical role in regulating energy metabolism, adipose stores and body weight, questions have been raised concerning the control of leptin synthesis and secretion and the function of leptin in controlling satiety and food intake. Basal or fasting leptin values are higher in women than men, increase during the course of pregnancy and, in both healthy adults and those with Type II (non-insulindependent) diabetes mellitus, are strongly correlated with per cent body fat or BMI [10,11] and adipose tissue mass [12±15].…”