Melanocortin-4 receptor activation inhibits c-Jun N-terminal kinase activity and promotes insulin signaling.
The melanocortin system is crucial to regulation of energy homeostasis. The melanocortin receptor type 4 (MC4R) modulates insulin signaling via effects on c-Jun N-terminal kinase (JNK). The melanocortin agonist NDP-MSH dose-dependently inhibited JNK activity in HEK293 cells stably expressing the human MC4R; effects were reversed by melanocortin receptor antagonist. NDP-MSH time- and dose-dependently inhibited IRS-1(ser307) phosphorylation, effects also reversed by a specific melanocortin receptor antagonist. NDP-MSH augmented insulin-stimulated AKT phosphorylation in vitro. The melanocortin agonist melanotan II increased insulin-stimulated AKT phosphorylation in the rat hypothalamus in vivo. NDP-MSH increased insulin-stimulated glucose uptake in hypothalamic GT1-1 cells. The current study shows that the melanocortinergic system interacts with insulin signaling via novel effects on JNK activity.
Chai
Biaoxin
B
Department of Surgery, University of Michigan, 2101 Taubman Center, Ann Arbor, MI 48109-0346, USA.
Li
Ji-Yao
JY
Zhang
Weizhen
W
Wang
Hui
H
Mulholland
Michael W
MW
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; C079282:melanotan-II; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases