Endocrine Abstracts

Lys-γ3-MSH is a melanocortin peptide derived from the C-terminal of the 16 kDa fragment of pro-opiomelanocortin (POMC). The physiological role of Lys-γ3-MSH is unclear, although it can potentiate the steroidogenic response of adrenal cortical cells to adrenocorticotrophin (ACTH). This effect appears to correlate with an ability to increase the activity of hormone sensitive lipase (HSL) and therefore the rate of cholesterol ester hydrolysis. Ligand binding studies have suggested the presence of binding sites for Lys-γ3-MSH on tissues that express HSL, including the adrenal and adipose tissue, suggesting Lys-γ3-MSH may play a wider role in cholesterol and lipid metabolism. In support of this hypothesis we found that in comparison to ACTH and α-MSH, Lys-γ3-MSH was a potent stimulator of lipolysis (measured by glycerol release) in mouse 3T3-L1 adipocyte cells. We also found that it stimulated a dose dependent phosphorylation of Perilipin A, a protein that is also critical for lipolysis. The melanocortin receptor (MCR) expressed by 3T3-L1 cells that binds Lys-γ3-MSH is unclear, since these cells have been shown to express only the Melanocortin (MC) 2 and 5 receptors that have no significant and very low affinity for Lys-γ3-MSH respectively. In experiments to investigate this further we found that neither the MC 1,3,4 and 5 receptor antagonist HS024 or NDP-α-MSH (an MCR agonist which has previously been shown (1) to bind to the MC5R in 3T3-L1 cells but not promote cAMP accumulation) had no effect on ACTH or Lys-γ3-MSH stimulated lipolysis but significantly reduced lipolysis stimulated by α-MSH. Since the MC2R shows no affinity for Lys-γ3-MSH, our results suggest that 3T3-L1 cells may either express an un-characterised MCR, or alternatively an MC2/MC5 hybrid with a high affinity for Lys-γ3-MSH.

1. Boston and Cone. Endocrinology 1996 137 2043–2050