Peripheral effect of alpha-melanocyte-stimulating hormone on fatty acid oxidation in skeletal muscle.
2007
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 (Melanotan II) 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. 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.
Five subtypes of MCR have been cloned and characterized. Among them,
MC3R, MC4R, and MC5R are known to be expressed in both the central nervous system and in peripheral tissues.
MC3R has been found in several nuclei of the hypothalamus, the pancreas, and the gastrointestinal tract;
MC4R is found throughout the brain, in the sympathetic nervous system, and in muscle; and
MC5R can be found in a broad spectrum of tissues, including the brain and skeletal muscle.
In conclusion, study demonstrates that a-MSH regulates FAO in skeletal muscle through the activation of MCRs, mainly MC5R, and the activation of AMPK. Our data show possible involvement of the melanocortin system in the regulation of lipid metabolism in skeletal muscle, independent of its well known effects in the central nervous system. Furthermore, our findings may provide valuable insight regarding potential melanocortin analogues that could be used to improve insulin sensitivity by stimulating FAO in skeletal muscle.
?-MSH signalling via melanocortin 5 receptor promotes lipolysis and impairs re-esterification in adipocytes
2013
Abstract
The melanocortin system has a clear effect on the mobilization of stored lipids in adipocytes. The aim of the current study was to investigate the role of melanocortin 5 receptor (MC5R) on ?-melanocyte-stimulating hormone (?-MSH)-induced lipolysis in 3T3-L1 adipocytes. To this end, MC5R expression was decreased by small interfering RNA (siRNA), which significantly impaired the ?-MSH stimulation of lipolysis, as determined by glycerol and nonesterified fatty-acid (NEFA) quantification. The functional role of ?-MSH/MC5R on triglyceride (TG) hydrolysis was mediated by hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), perilipin 1 (PLIN1) and acetyl-CoA carboxylase (ACC). Immunofluorescence microscopy revealed that phosphorylated HSL clearly surrounded lipid droplets in ?-MSH-stimulated adipocytes, whereas PLIN1 left the immediate periphery of lipids. These observations were lost when the expression of MC5R was suppressed.
In 3T3-L1 adipocytes, ?-MSH-activated MC5R signals through the cAMP/PKA and MAPK/ERK1/2 pathways. PKA was fundamental for HSL and PLIN1 activation and lipolysis regulation. ERK1/2 inhibition strongly interfered with the release of NEFAs but not glycerol. In addition, the intracellular TG levels, which were decreased after MC5R activation, were restored after ERK1/2 inhibition, indicating that these kinases are involved in NEFA re-esterification rather than lipolysis regulation. This notion is also supported by the observation that the ?-MSH-mediated activation of phosphoenolpyruvate carboxykinase (PEPCK) was abolished in the presence of ERK1/2 inhibitors.
Altogether, these results indicate that ?-MSH-activated MC5R regulates two tightly coupled pathways in adipocytes: lipolysis and re-esterification. The global effect is a decrease in adipocyte fat mass, which is important for strategies to ameliorate obesity.
Melanocortins are known to decrease body weight. But its implications in obesity are not yet explored. I think such patients suffering from obesity can benefit from taking melanocortins. With proper diet, exercise and melanocortins, achieving a desired body weight can be easier and realistic. But again, there has to be certain boundaries as the person might take off too much weight or become dependent on it. Moderation and balance is the key.
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