Prolylcarboxypeptidase regulates food intake by inactivating alpha-MSH in rodents

J Clin Invest. 2009 Aug;119(8):2291-303. doi: 10.1172/JCI37209. Epub 2009 Jul 20.


The anorexigenic neuromodulator alpha-melanocyte-stimulating hormone (alpha-MSH; referred to here as alpha-MSH1-13) undergoes extensive posttranslational processing, and its in vivo activity is short lived due to rapid inactivation. The enzymatic control of alpha-MSH1-13 maturation and inactivation is incompletely understood. Here we have provided insight into alpha-MSH1-13 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. Real-time 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 alpha-MSH1-13, producing alpha-MSH1-12, which is not neuroactive. We found that Prcp was expressed in the hypothalamus in neuronal populations that send efferents to areas where alpha-MSH1-13 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 alpha-MSH1-13 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 alpha-MSH1-13 levels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxypeptidases / antagonists & inhibitors
  • Carboxypeptidases / genetics
  • Carboxypeptidases / physiology*
  • Eating* / drug effects
  • Enzyme Inhibitors / pharmacology
  • Female
  • Hypothalamus / metabolism
  • Male
  • Melanocyte-Stimulating Hormones / metabolism
  • Melanocyte-Stimulating Hormones / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Obesity / etiology
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Polymerase Chain Reaction
  • Pyrimidines / pharmacology
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Melanocortin / physiology
  • alpha-MSH / antagonists & inhibitors*
  • alpha-MSH / physiology


  • Enzyme Inhibitors
  • Peptide Fragments
  • Pyrimidines
  • RNA, Messenger
  • Receptors, Melanocortin
  • benzopyridopyrimidine
  • alpha-MSH
  • MSH (11-13)
  • Melanocyte-Stimulating Hormones
  • Carboxypeptidases
  • lysosomal Pro-X carboxypeptidase