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
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
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Research Article

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. 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 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-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 α-MSH1–13 levels.

Authors

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

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Figure 6

Effect of α-MSH1–13 and α-MSH1–12 on food intake.

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Effect of α-MSH1–13 and α-MSH1–12 on food intake. (A) Graph showing ...
(A) Graph showing the effect of i.c.v. injection of 2.5 μg of α-MSH1–13 and α-MSH1–12 on food intake compared with saline control (n = 6 in both groups). Means (± SEM) were compared using 1-way ANOVA followed by the Student-Newman-Keuls method. *P = 0.006. (B and C) Electrophysiology results of α-MSH1–13 (B) and α-MSH1–12 (C) on GFP-MC4R neurons of the PVN of the hypothalamus (n = 9). Data represent the mean ± SEM. †P = 0.024. (D) Effect of i.c.v. administration of vehicle and 0.9 mg BPP on food intake of fasted rats (n = 6 for each group). Data represent the mean ± SEM. Statistical analysis was performed by unpaired t test. ‡P = 0.016. (E) Percentage of food intake in Lepob/ob mice injected i.p. with vehicle (white bars; n = 5) and with 400 μg of BPP (black bars; n = 5). Data represent the mean ± SEM. Statistical analysis was performed by unpaired t test. #P = 0.022, ##P = 0.039. (F) Inhibitory effect on food intake of i.p. administration of ZPP. ZPP produced a specific dose-responsive inhibition of food intake in overnight-fasted mice. Significance value indicated for individual time points represents 100 mg/kg BW versus vehicle. Data represent the mean ± SEM. **P = 0.0025, §P < 0.05. (G) Percentage of food intake in Lepob/ob mice injected i.p. with vehicle (white bars; n = 5) and with 100 mg/kg BW of ZPP (black bars; n = 5). The data represent the mean ± SEM. Statistical analysis was performed by unpaired t test. P = 0.006, ††P = 0.047. (H) Intracerebroventricularly injected SHU9119 (6 nmol) specifically blocks ZPP inhibition of food intake. Significance value indicated for individual time point represents vehicle/ZPP versus SHU9119/ZPP. Data represent the mean ± SEM. ‡‡P = 0.0025 for treatment and P = 0.0002 for time points.