Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

The melanocortin receptors (MCRs) belong to the G-protein coupled receptors (family A). So far, 5 different subtypes have been described (MC1R–MC5R) and of these MC2R and MC5R have been proposed to act directly in adipocytes and regulate lipolysis in rodents. Using ACTH and α-melanocyte stimulating hormone (α-MSH) generated from proopiomelanocortin (POMC), as well as synthetic MSH analogues to stimulate lipolysis in murine 3T3-L1 adipocytes it is shown that MC2R and MC5R are lipolytic mediators in differentiated 3T3-L1 adipocytes. Involvement of cAMP, phosphorylated extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (PKB), adenosine 5′ monophosphate activated protein kinase (AMPK) and Jun-amino-terminal kinase (JNK) in MCR mediated lipolysis were studied. Interestingly, results obtained in 3T3-L1 cells suggest that lipolysis stimulated by α-MSH, NDP-α-MSH, MT-II, SHU9119 and PG-901 is mediated through MC5R in a cAMP independent manner. Finally, we identify essential differences in MCR mediated lipolysis when using 3T3-L1 cells compared to primary adipocytes.

► α-MSH, NDP-α-MSH, MT-II, SHU9119 and PG-901 stimulation of lipolysis in differentiated murine 3T3-L1 is mediated through MC5R independently of cAMP.
► Essential differences in MCR mediated lipolysis are found between 3T3-L1 cells and murine primary adipocytes.
► Lipolysis stimulated by α-MSH is antagonized by PG-901 and NDP-α-MSH in primary adipocytes. This indicates that in some cases the agonist NDP-α-MSH works as an antagonist.
► This study supports a peripheral regulation of adipocyte metabolism by the melanocortin system in addition to neuronal regulation.