Prolylcarboxypeptidase (PRCP) as a new target for obesity treatment

Abstract

Recently, we serendipitously discovered that mice with the deficiency of the enzyme prolylcarboxypeptidase (PRCP) have elevated alpha-melanocyte-stimulating hormone (alpha-MSH) levels which lead to decreased food intake and weight loss. This suggests that PRCP is an endogenous inactivator of alpha-MSH and an appetite stimulant. Since a modest weight loss can have the most profound influence on reducing cardiovascular risk factors, the inhibitors of PRCP would be emerging as a possible alternative for pharmacotherapy in high-risk patients with obesity and obesity-related disorders. The discovery of a new biological activity of PRCP in the PRCP-deficient mice and studies of alpha-MSH function indicate the importance and complexity of the hypothalamic pro-opiomelanocortin (POMC) system in altering food intake. Identifying a role for PRCP in regulating alpha-MSH in the brain may be a critical step in enhancing our understanding of how the brain controls food intake and body weight. In light of recent findings, the potential role of PRCP in regulating fuel homeostasis is critically evaluated. Further studies of the role of PRCP in obesity are much needed.

Figure 1

The physiological action of prolylcarboxypeptidase (PRCP). Notes: PRCP elicits increased production of proinflammatory prostaglandins and vasodilatory nitric oxide and promotes orexigenic action through inactivation of α-MSH. Abbreviations: α-MSH, α-melanocyte-stimulating hormone; HK high molecular weight kininogen; PK, prekallikrein.

Figure 2

The role of the hypothalamus in food intake and metabolism. Notes: The catalysis of α-MSH_1–13 to α-MSH_1–12 by PRCP leads to increased food intake and body weight gain in humans. Blue arrows indicate anorectic response and red arrows indicate orexigenic response. Abbreviations: Act-α-MSH, acetylated α-MSH; AgRP, Agouti-related protein; ARC, arcuate nucleus of the hypothalamus; Des-α-MSH, desacetyl α-MSH; DM, dorsomedial hypothalamus; GABA, gamma-aminobutryric acid; LH, lateral hypothalamus; MC3R, melanocortin-3 receptor; MC4R, melanocortin-4 receptor; NPY, neuropetide y; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus.

Figure 3

Schematic structure of pro-opiomelanocortin (POMC) and location of melanocyte-stimulating hormones (MSH). Abbreviations: ACTH, adrenocorticotropic hormone; β-LPH, beta-lipotropic hormone; S, signal sequence; γ-MSH, gamma-MSH; α-MSH, alpha-MSH; β-MSH, beta-MSH; β-endorphin, beta-endorphin.

Figure 4

PRCP inhibitors provoke accumulation of α-MSH_1–13 peptide leading to reduced body weight, inflammation, and pain. Abbreviations: α-MSH_1–13, a proopiomelanocortin (POMC) cleavage product; MC4R, melanocortin-4 receptor; MC1R, melanocortin-1 receptor; predominant receptors of α-MSH_1–13; AgRP, agouti-related protein; endogenous MC4R antagonist; MTII, MC4R agonist; and prolylcarboxypeptidase (PRCP), endogenous inactivator of α-MSH_1–13.