Direct evidence for leptin-induced lipid oxidation independent of long-form leptin receptor

Abstract

Leptin administration has been shown to enhance muscle lipid oxidation in relation to the energy expenditure. Both long-form (Ob-R L) and short-form leptin receptors (Ob-R S) are expressed in skeletal muscle, but the role of Ob-R S is unclear. In the present study, the role of Ob-R S in leptin-induced lipid oxidation in skeletal muscles was investigated using primary murine myotubes from m/m and db/db mice. Primary myotubes were treated with leptin (0.1, 1, 10, 100 nM) for 24 h. Lipid oxidation was determined by 14CO 2 production rate from [1- 14C] palmitate. Leptin was found to increase lipid oxidation in a dose- and time-dependent manner in db/db myotubes as well as in m/m myotubes. Leptin significantly increased phosphorylation of JAK2 and STAT3 in both types of myotube. Leptin-induced lipid oxidation was abolished by STAT3 siRNA. To investigate the mechanism underlying leptin-induced lipid oxidation, the effects of pharmacological inhibitors were examined. JAK2 or p38 MAPK inhibitor suppressed leptin-induced lipid oxidation and decreased STAT3 phosphorylation in both types of myotube, respectively. Leptin significantly increased phosphorylation of p38 MAPK, and leptin-induced lipid oxidation was abolished by treatment with p38 MAPK siRNA in both types of myotube. These results suggest that leptin induces lipid oxidation in skeletal muscle through the JAK2/p38 MAPK/STAT3 signaling pathway via not only Ob-R L but also Ob-R S.