Direct evidence for leptin-induced lipid oxidation independent of long-form leptin receptor.
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, 100nM) for 24h. Lipid oxidation was determined by (14)CO(2) production rate from [1-(14)C] 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).
Akasaka
Yunike
Y
Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1 Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Tsunoda
Masaki
M
Ogata
Tomomi
T
Ide
Tomohiro
T
Murakami
Koji
K
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology; D018482:Muscle, Skeletal / Q000166:cytology; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D005227:Fatty Acids; D020738:Leptin; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases