Pro-opiomelanocortin (POMC) is cleaved into multiple peptides, the mix of which is tissue and cell-type dependent. The multiple POMC-derived peptides have a diverse array of physiological functions including the stress response, pigmentation, immune response, anxiety and energy homeostasis through specific binding of five melanocortin receptor (MCR) subtypes and regulation of their signal transduction pathways. In recent years there has been much focus on understanding roles for the MC3R and MC4R in the regulation of body weight and metabolism. Both MC3R and MC4R are expressed in brain and in the periphery. Functional MC3R and MC4R are known to be critical for normal body weight regulation in mice and a functional MC4R is known to be critical for human body weight regulation. It is widely assumed that α-melanocyte stimulating hormone (α-MSH) is the endogenous POMC-derived peptide responsible for body weight regulation and yet this has not been conclusively demonstrated. Desacetyl-α-MSH is more abundant than α-MSH in human and rodent brains and in human blood, and its physiological importance has not yet been realized. Several POMC-derived peptides (adrenocorticotropin {ACTH}, α-MSH, desacetyl-α-MSH and β-MSH) bind and activate MC3R and MC4R similarly in vitro but it is unclear which of these peptides are critical for body weight regulation. My research group is focused on understanding functions for specific POMC-derived peptides using a knock-in mouse model with a mutation in the POMC cleavage site that is required to generate ACTH1-13, the precursor for both desacetyl-α-MSH and α-MSH. Identification of specific POMC-derived peptide functions will advance understanding of the endogenous melanocortin system and may open up new therapeutic strategies to treat obesity.
Funding provided by The Marsden Fund, Auckland Medical Research Fund and Faculty Research and Development Fund.