Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents

Abstract

The anorexigenic neuromodulator α-melanocyte-stimulating hormone (α-MSH; referred to here as α-MSH 1-13 ) undergoes extensive posttranslational processing, and its in vivo activity is short lived due to rapid inactivation. The enzymatic control of α-MSH 1-13 maturation and inactivation is incompletely understood. Here we have provided insight into α-MSH 1-13 inactivation through the generation and analysis of a subcongenic mouse strain with reduced body fat compared with controls. Using positional cloning, we identified a maximum of 6 coding genes, including that encoding prolylcarboxypeptidase (PRCP), in the donor region. Realtime PCR revealed a marked genotype effect on Prcp mRNA expression in brain tissue. Biochemical studies using recombinant PRCP demonstrated that PRCP removes the C-terminal amino acid of α-MSH 1-13 , producing α-MSH 1-12 , which is not neuroactive. We found that Prcp was expressed in the hypothalamus in neuronal populations that send efferents to areas where α-MSH 1-13 is released from axon terminals. The inhibition of PRCP activity by small molecule protease inhibitors administered peripherally or centrally decreased food intake in both wild-type and obese mice. Furthermore, Prcp-null mice had elevated levels of α-MSH 1-13 in the hypothalamus and were leaner and shorter than the wild-type controls on a regular chow diet; they were also resistant to high-fat diet-induced obesity. Our results suggest that PRCP is an important component of melanocortin signaling and weight maintenance via control of active α-MSH 1-13 levels.

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

“…Furthermore, prolylcarboxypeptidase have been shown to regulate food intake by inactivating -MSH centrally. It is plausible that similar mechanisms might regulate effects of the melanocortin system in the periphery (Wallingford et al 2009).…”

The Prolyl Peptidases PRCP/PREP Regulate IRS-1 Stability Critical for Rapamycin-induced Feedback Activation of PI3K and AKT

“…Another family member, prolyl endopeptidase (PREP), has a high degree of sequence similarity, and is phylogenetically close to PRCP (22). PREP cleaves known PRCP substrates angiotensin (Ang) II/III and ␣-melanocyte stimulating hormone (MSH) (23,24), as well as neurotensin (NTS), cholecystokinin, and gastrin-releasing peptides (25). These peptides are ligands for a number of G-protein coupled receptors (GPCR) such as angiotensin receptors and neurotensin receptors which can cross talk with IR/IGF-1R, and play a critical role in pancreatic cancer development in animal models (26,27).…”

Functional Genomic Architecture of Predisposition to Voluntary Exercise in Mice: Expression QTL in the Brain

“…7, a region contained within the confidence intervals of previously (see Kelly et al 2010b) identified QTL for running distance and duration (see Figure 3C and Kelly et al 2010b). Wallingford et al (2009) observed that the inhibition of Prcp activity in vivo decreased food intake in wild-type and obese mice, and Prcp-null mice were leaner and shorter than wild-type controls and resistant to high-fat diet-induced obesity (Wallingford et al 2009). Similar phenotypes have been observed in the HR strain of mice utilized here (Swallow et al 1999;Kelly et al 2006;Vaanholt et al 2008).…”