title: Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet.
abstract: Little is known about the role of the central melanocortin system in the control of fuel metabolism in peripheral tissues. Skeletal muscle AMP-activated protein kinase (AMPK) is activated by leptin and serves as a master regulator of fatty acid beta-oxidation. To elucidate an unidentified role of the central melanocortin system in muscle AMPK regulation, we treated conscious, unrestrained mice intracerebroventricularly with the melanocortin agonist MT-II or the antagonist SHU9119. MT-II augmented phosphorylation of AMPK and its target acetyl-CoA carboxylase (ACC) independent of caloric intake. Conversely, AMPK/ACC phosphorylation by leptin was abrogated by the coadministration of SHU9119 or in KKA(y) mice, which centrally express endogenous melanocortin antagonist. Importantly, high-fat-diet-induced attenuation of AMPK/ACC phosphorylation in leptin-overexpressing transgenic mice was not reversed by central leptin but was markedly restored by MT-II. Our data provide evidence for the critical role of the central melanocortin system in the leptin-skeletal muscle AMPK axis and highlight the system as a therapeutic target in leptin resistance.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masuzaki
authors.forename: Shintaro
authors.initials: S
authors.lastname: Yasue
authors.forename: Ken
authors.initials: K
authors.lastname: Ebihara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiuchi
authors.forename: Takako
authors.initials: T
authors.lastname: Ishii
authors.forename: Naoki
authors.initials: N
authors.lastname: Arai
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hirata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hayashi
authors.forename: Kiminori
authors.initials: K
authors.lastname: Hosoda
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D004041:Dietary Fats; D020738:Leptin / Q000378:metabolism; D053486:Melanocortins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D008668:Metallothionein / Q000494:pharmacology; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D004041:Dietary Fats; D020738:Leptin; D053486:Melanocortins; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones; D008668:Metallothionein; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases