Peripheral effect of alpha-melanocyte-stimulating hormone on fatty acid oxidation in skeletal muscle.
To study the peripheral effects of melanocortin on fuel homeostasis in skeletal muscle, we assessed palmitate oxidation and AMP kinase activity in alpha-melanocyte-stimulating hormone (alpha-MSH)-treated muscle cells. After alpha-MSH treatment, carnitine palmitoyltransferase-1 and fatty acid oxidation (FAO) increased in a dose-dependent manner. A strong melanocortin agonist, NDP-MSH, also stimulated FAO in primary culture muscle cells and C2C12 cells. However, [Glu6]alpha-MSH-ND, which has ample MC4R and MC3R agonistic activity, stimulated FAO only at high concentrations (10(-5) M). JKC-363, a selective MC4R antagonist, did not suppress alpha-MSH-induced FAO. Meanwhile, SHU9119, which has both antagonistic activity on MC3R and MC4R and agonistic activity on both MC1R and MC5R, increased the effect of alpha-MSH on FAO in both C2C12 and primary muscle cells. Small interference RNA against MC5R suppressed the alpha-MSH-induced FAO effectively. cAMP analogues mimicked the effect of alpha-MSH on FAO, and the effects of both alpha-MSH and cAMP analogue-mediated FAO were antagonized by a protein kinase A inhibitor (H89) and a cAMP antagonist ((Rp)-cAMP). Acetyl-CoA carboxylase activity was suppressed by alpha-MSH and cAMP analogues by phosphorylation through AMP-activated protein kinase activation in C2C12 cells. Taken together, these results suggest that alpha-MSH increases FAO in skeletal muscle, in which MC5R may play a major role. Furthermore, these results suggest that alpha-MSH-induced FAO involves cAMP-protein kinase A-mediated AMP-activated protein kinase activation.
An
Juan Ji
JJ
Department of Internal Medicine & Endocrine Research Institute, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemoon-Gu, Seoul 120-752, Korea.
Rhee
Yumie
Y
Kim
Se Hwa
SH
Kim
Dol Mi
DM
Han
Dong-He
DH
Hwang
Jung Hee
JH
Jin
Young-Jun
YJ
Cha
Bong Soo
BS
Baik
Ja-Hyun
JH
Lee
Won Tae
WT
Lim
Sung-Kil
SK
D000818:Animals; D002478:Cells, Cultured; D017931:DNA Primers; D005227:Fatty Acids / Q000378:metabolism*; D006614:Hindlimb; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000521:alpha-MSH / Q000494:pharmacology*
D017931:DNA Primers; D005227:Fatty Acids; D044102:Receptor, Melanocortin, Type 1; D011994:Recombinant Proteins; D000521:alpha-MSH