Obesity, POMC, and POMC-processing Enzymes: Surprising Results From Animal Models

Abstract

Peptides derived from proopiomelanocortin (POMC) are well-established neuropeptides and peptide hormones that perform multiple functions, including regulation of body weight. In humans and some animals, these peptides include α- and β-melanocyte-stimulating hormone (MSH). In certain rodent species, no β-MSH is produced from POMC because of a change in the cleavage site. Enzymes that convert POMC into MSH include prohormone convertases (PCs), carboxypeptidases (CPs), and peptidyl-α-amidating monooxygenase (PAM). Humans and mice with inactivating mutations in either PC1/3 or carboxypeptidase E (CPE) are obese, which was assumed to result from defective processing of POMC into MSH. However, recent studies have shown that selective loss of either PC1/3 or CPE in POMC-expressing cells does not cause obesity. These findings suggest that defects in POMC processing cannot alone account for the obesity observed in global PC1/3 or CPE mutants. We propose that obesity in animals lacking PC1/3 or CPE activity depends, at least in part, on deficient processing of peptides in non-POMC-expressing cells either in the brain and/or the periphery. Genetic background may also contribute to the manifestation of obesity.

Keywords: PC1/3; PC2; POMC; carboxypeptidase E; obesity; proprotein convertase.

Figure 1.

Diagram of proopiomelanocortin (POMC) and major human POMC-derived peptides. Mice, rats, and some (but not all rodents) have differences in the consensus cleavages sites necessary to produce γ1MSH and βMSH, and as a result these 2 peptides are not detected in mouse hypothalamus or pituitary, although a shorter form of γ1MSH resulting from cleavage at an RxxR-F bond is detected in peptidomic studies of mouse brain and pituitary (2). A consensus site for Ser phosphorylation is present both in humans and mice (phosph), as well as N-glycosylation sites (not shown). The highly conserved N-terminal region has 2 intramolecular disulfide bonds (not shown). The numbers refer to the position within prePOMC (ie, the form containing the signal peptide). In addition to the indicated forms, other major forms include di-acetylated αMSH and acetylated β-endorphin. The opioid receptor-binding pentapeptide of β-endorphin (YGGFM) is highlighted in red, and the melanocortin receptor-binding tetrapeptide motif (HFRW) is highlighted in blue. αMSH, α–melanocyte-stimulating hormone; CLIP, corticotropin-like intermediate lobe peptide; End, endorphin; J-peptide, joining peptide; LPH, lipotropin.