Prolylcarboxypeptidase regulates food intake by inactivating alpha-MSH in rodents.
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.
Wallingford
Nicholas
N
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA.
Perroud
Bertrand
B
Gao
Qian
Q
Coppola
Anna
A
Gyengesi
Erika
E
Liu
Zhong-Wu
ZW
Gao
Xiao-Bing
XB
Diament
Adam
A
Haus
Kari A
KA
Shariat-Madar
Zia
Z
Mahdi
Fakhri
F
Wardlaw
Sharon L
SL
Schmaier
Alvin H
AH
Warden
Craig H
CH
Diano
Sabrina
S
D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009765:Obesity / Q000209:etiology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044101:Receptors, Melanocortin / Q000502:physiology; D000521:alpha-MSH / Q000037:antagonists & inhibitors* / Q000502:physiology
D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011743:Pyrimidines; D012333:RNA, Messenger; D044101:Receptors, Melanocortin; C474393:benzopyridopyrimidine; D000521:alpha-MSH; C043156:MSH (11-13); D009074:Melanocyte-Stimulating Hormones; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase