Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents

Nicholas Wallingford, Bertrand Perroud, Qian Gao, Anna Coppola, Erika Gyengesi, Zhong Wu Liu, Xiao Bing Gao, Adam Diament, Kari A. Haus, Zia Shariat-Madar, Fakhri Mahdi, Sharon L. Wardlaw, Alvin H. Schmaier, Craig H Warden, Sabrina Diano

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)2291-2303
Number of pages13
JournalJournal of Clinical Investigation
Volume119
Issue number8
DOIs
StatePublished - Aug 3 2009

Fingerprint

lysosomal Pro-X carboxypeptidase
Melanocyte-Stimulating Hormones
Rodentia
Eating
Hypothalamus
Melanocortins
Obese Mice
Presynaptic Terminals
High Fat Diet
Protease Inhibitors
Neurotransmitter Agents
Adipose Tissue
Organism Cloning
Obesity
Genotype
Maintenance
Diet
Amino Acids
Weights and Measures
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Wallingford, N., Perroud, B., Gao, Q., Coppola, A., Gyengesi, E., Liu, Z. W., ... Diano, S. (2009). Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents. Journal of Clinical Investigation, 119(8), 2291-2303. https://doi.org/10.1172/JCI37209

Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents. / Wallingford, Nicholas; Perroud, Bertrand; Gao, Qian; Coppola, Anna; Gyengesi, Erika; Liu, Zhong Wu; Gao, Xiao Bing; Diament, Adam; Haus, Kari A.; Shariat-Madar, Zia; Mahdi, Fakhri; Wardlaw, Sharon L.; Schmaier, Alvin H.; Warden, Craig H; Diano, Sabrina.

In: Journal of Clinical Investigation, Vol. 119, No. 8, 03.08.2009, p. 2291-2303.

Research output: Contribution to journalArticle

Wallingford, N, Perroud, B, Gao, Q, Coppola, A, Gyengesi, E, Liu, ZW, Gao, XB, Diament, A, Haus, KA, Shariat-Madar, Z, Mahdi, F, Wardlaw, SL, Schmaier, AH, Warden, CH & Diano, S 2009, 'Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents', Journal of Clinical Investigation, vol. 119, no. 8, pp. 2291-2303. https://doi.org/10.1172/JCI37209
Wallingford N, Perroud B, Gao Q, Coppola A, Gyengesi E, Liu ZW et al. Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents. Journal of Clinical Investigation. 2009 Aug 3;119(8):2291-2303. https://doi.org/10.1172/JCI37209
Wallingford, Nicholas ; Perroud, Bertrand ; Gao, Qian ; Coppola, Anna ; Gyengesi, Erika ; Liu, Zhong Wu ; Gao, Xiao Bing ; Diament, Adam ; Haus, Kari A. ; Shariat-Madar, Zia ; Mahdi, Fakhri ; Wardlaw, Sharon L. ; Schmaier, Alvin H. ; Warden, Craig H ; Diano, Sabrina. / Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 8. pp. 2291-2303.
@article{d052c167396542bc898ac02db8e86640,
title = "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-MSH1-13) undergoes extensive posttranslational processing, and its in vivo activity is short lived due to rapid inactivation. The enzymatic control of α-MSH1-13 maturation and inactivation is incompletely understood. Here we have provided insight into α-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. 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-MSH1-13, producing α-MSH1-12, which is not neuroactive. We found that Prcp was expressed in the hypothalamus in neuronal populations that send efferents to areas where α-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 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-MSH1-13 levels.",
author = "Nicholas Wallingford and Bertrand Perroud and Qian Gao and Anna Coppola and Erika Gyengesi and Liu, {Zhong Wu} and Gao, {Xiao Bing} and Adam Diament and Haus, {Kari A.} and Zia Shariat-Madar and Fakhri Mahdi and Wardlaw, {Sharon L.} and Schmaier, {Alvin H.} and Warden, {Craig H} and Sabrina Diano",
year = "2009",
month = "8",
day = "3",
doi = "10.1172/JCI37209",
language = "English (US)",
volume = "119",
pages = "2291--2303",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "8",

}

TY - JOUR

T1 - Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents

AU - Wallingford, Nicholas

AU - Perroud, Bertrand

AU - Gao, Qian

AU - Coppola, Anna

AU - Gyengesi, Erika

AU - Liu, Zhong Wu

AU - Gao, Xiao Bing

AU - Diament, Adam

AU - Haus, Kari A.

AU - Shariat-Madar, Zia

AU - Mahdi, Fakhri

AU - Wardlaw, Sharon L.

AU - Schmaier, Alvin H.

AU - Warden, Craig H

AU - Diano, Sabrina

PY - 2009/8/3

Y1 - 2009/8/3

N2 - The anorexigenic neuromodulator α-melanocyte-stimulating hormone (α-MSH; referred to here as α-MSH1-13) undergoes extensive posttranslational processing, and its in vivo activity is short lived due to rapid inactivation. The enzymatic control of α-MSH1-13 maturation and inactivation is incompletely understood. Here we have provided insight into α-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. 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-MSH1-13, producing α-MSH1-12, which is not neuroactive. We found that Prcp was expressed in the hypothalamus in neuronal populations that send efferents to areas where α-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 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-MSH1-13 levels.

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

UR - http://www.scopus.com/inward/record.url?scp=68849092560&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68849092560&partnerID=8YFLogxK

U2 - 10.1172/JCI37209

DO - 10.1172/JCI37209

M3 - Article

C2 - 19620781

AN - SCOPUS:68849092560

VL - 119

SP - 2291

EP - 2303

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 8

ER -