Peripheral Effect of α-Melanocyte-stimulating Hormone on Fatty Acid Oxidation in Skeletal Muscle

Bong Soo Cha,Se Hwa Kim,Dong-He Han,Dol Mi Kim,Juan Ji An,Sung-Kil Lim,Yumie Rhee,Jung Hee Hwang,Ja-Hyun Baik,Young-Jun Jin,Won Tae Lee

doi:10.1074/jbc.m603454200

Abstract

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.

Highlights

Obesity is a major health problem in humans; it is associated with an increased risk of type 2 diabetes, as well as with cardiovascular and cerebrovascular diseases
Our data demonstrate that ␣-MSH increased fatty acid oxidation (FAO) in a dosedependent manner in mouse skeletal muscle and C2C12 cells
We suggest that MC5R is the most probable subtype involved in inducing FAO in skeletal muscle, possibly via the cAMP-PKA-AMPK-acetyl-CoA carboxylase (ACC) pathway

Summary

Introduction

Obesity is a major health problem in humans; it is associated with an increased risk of type 2 diabetes, as well as with cardiovascular and cerebrovascular diseases. We showed that ␣-MSH regulates FAO through the activation of the MCR-mediated protein kinase A (PKA)-AMPK signal transduction pathway in skeletal muscle. The effect siRNA against either MC1R or MC3R failed to show any visible of ␣-MSH on palmitate oxidation was measured in C2C12 suppression of ␣-MSH induced FAO in these cells (Fig. 4B).

Results

Conclusion