Lys-gamma3-MSH is a peptide derived from the multihormone precursor protein pro-opiomelanocortin (POMC). Lys-gamma3-MSH increases cholesterol ester hydrolysis and mitochondrial cholesterol accumulation in the adrenal gland by activating the enzyme cholesterol ester hydrolase (CEH). Although the receptor through which the actions of Lys-gamma3-MSH on the adrenal gland are mediated remains to be identified, ligand binding studies suggest the existence of binding sites in adipose tissue, skeletal muscle, testis, adrenal, cardiac muscle and ovary . Recently the enzyme responsible for hormone-mediated lipolysis in the adipocyte, hormone sensitive lipase (HSL) has been shown to be the same enzyme as adrenal CEH . Since the tissue expression profile of HSL closely matches the tissue binding profile for Lys-gamma3-MSH, it is possible that this peptide may regulate the activity of HSL in tissues other than the adrenal. To investigate this we analysed the actions of Lys-gamma3-MSH peptides on HSL activity in the adipocyte using the 3T3-L1 adipocyte cell line. Lipolysis, as determined by glycerol release, in 3T3-L1 adipocytes was significantly increased by Lys-gamma3-MSH at doses of 1 nM or above. As in the adrenal gland the receptor through which the actions of Lys-gamma3-MSH on 3T3-L1 adipocytes are mediated is unknown. 3T3-L1 adipocytes have been shown to express both the MC2R and MC5-R but not the MC1R, MC3R or MC4R . Since gamma-MSH peptides have no significant affinity for the MC2R, and exhibit low affinity for the MC5-R, the actions of Lys-gamma3-MSH potentially highlight the existence of a novel melanocortin receptor. Furthermore these results indicate that the actions of Lys-gamma3-MSH are not limited to the adrenal, but may play a broader role in regulating HSL activity, cholesterol and lipid utilisation in a variety of tissues.
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04 - 06 Apr 2005
British Endocrine Societies