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 language | English (US) |
|---|---|
| Pages (from-to) | 2291-2303 |
| Number of pages | 13 |
| Journal | Journal of Clinical Investigation |
| Volume | 119 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 3 2009 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
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 -