Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Line
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Dose-Response Relationship, Drug
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Humans
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Hypothalamus / metabolism
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Insulin / metabolism*
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Insulin / pharmacology
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Insulin Receptor Substrate Proteins / antagonists & inhibitors
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Insulin Receptor Substrate Proteins / metabolism
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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JNK Mitogen-Activated Protein Kinases / metabolism
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Peptides, Cyclic / pharmacology
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Phosphorylation
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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptor, Melanocortin, Type 4 / agonists*
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Receptor, Melanocortin, Type 4 / biosynthesis
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Receptor, Melanocortin, Type 4 / metabolism*
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Signal Transduction*
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Time Factors
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alpha-MSH / analogs & derivatives*
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alpha-MSH / pharmacology
Substances
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IRS1 protein, human
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Insulin
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Insulin Receptor Substrate Proteins
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Peptides, Cyclic
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Receptor, Melanocortin, Type 4
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melanotan-II
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alpha-MSH
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MSH, 4-Nle-7-Phe-alpha-
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases