Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet.
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.
Tanaka
Tomohiro
T
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Masuzaki
Hiroaki
H
Yasue
Shintaro
S
Ebihara
Ken
K
Shiuchi
Tetsuya
T
Ishii
Takako
T
Arai
Naoki
N
Hirata
Masakazu
M
Yamamoto
Hiroshi
H
Hayashi
Tatsuya
T
Hosoda
Kiminori
K
Minokoshi
Yasuhiko
Y
Nakao
Kazuwa
K
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*
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