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The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake

Nature Medicine volume 15, pages 1195–1201 (2009)Cite this article

Abstract

Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity after weight loss. Insulin and leptin inhibit food intake through actions in the central nervous system that are partly mediated by the transcription factor FoxO1. We show that FoxO1 ablation in pro-opiomelanocortin (Pomc)-expressing neurons in mice (here called Pomc-Foxo1−/− mice) increases Carboxypeptidase E (Cpe) expression, resulting in selective increases of α-melanocyte–stimulating hormone (α-Msh) and carboxy-cleaved β-endorphin, the products of Cpe-dependent processing of Pomc. This neuropeptide profile is associated with decreased food intake and normal energy expenditure in Pomc-Foxo1−/− mice. We show that Cpe expression is downregulated by diet-induced obesity and that FoxO1 deletion offsets the decrease, protecting against weight gain. Moreover, moderate Cpe overexpression in the arcuate nucleus phenocopies features of the FoxO1 mutation. The dissociation of food intake from energy expenditure in Pomc-Foxo1−/− mice represents a model for therapeutic intervention in obesity and raises the possibility of targeting Cpe to develop weight loss medications.

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Figure 1: Body weight and composition.
Figure 2: Food intake and leptin sensitivity.
Figure 3: Evidence of altered Cpe activity in Pomc-Foxo1−/− mice.
Figure 4: Regulation of Cpe by diet and calorie restriction.
Figure 5: Regulation of Pc-1 and Cpe expression.

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Acknowledgements

Supported by Deutsche Forschungsgemeinschaft PL542/1-1 (L.P.), US National Institutes of Health DK57539 and DK58282 (D.A.), DK80003 (S.L.W.) and DK63608 (Columbia Diabetes and Endocrinology Research Center). We thank R. Leibel for insightful discussions, L. Zeltser and S. Padilla for help with in situ hybridization, N. Seidah (Clinical Research Institute of Montreal) and D. Good (University of Massachusetts) for plasmids encoding pCsk1, A. White (University of Manchester) for neuropeptide antisera, and M. Low (Oregon Health Sciences University) for Pomc-Gfp transgenic mice, Y. Liu for technical assistance and members of the Accili and Wardlaw laboratories for stimulating discussions. R.A.D. is an American Cancer Society Research Professor and an Ellison Medical Foundation Senior Scholar and is supported by the Robert A. and Renee E. Belfer Family Institute for Innovative Cancer Science.

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  1. Leona Plum

    Present address: Present address: Department of Clinical Research, Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany.,

Authors and Affiliations

  1. Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York, USA

    Leona Plum, Hua V Lin, Roxanne Dutia, Jun Tanaka, Kumiko S Aizawa, Michihiro Matsumoto, Andrea J Kim, Sharon L Wardlaw & Domenico Accili

  2. Department of Clinical Pharmacology, International Medical Center of Japan, Tokyo, Japan

    Michihiro Matsumoto

  3. Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA

    Niamh X Cawley & Y Peng Loh

  4. Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine, and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Ji-Hye Paik & Ronald A DePinho

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Contributions

L.P., H.V.L., R.D., J.T., K.S.A., M.M., A.J.K. and S.L.W. performed experiments and analyzed data. N.X.C. and J.-H.P. generated reagents used for experiments. L.P., H.V.L., Y.P.L., R.A.D., S.L.W. and D.A. designed the studies, analyzed the data and wrote the manuscript.

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Correspondence to Domenico Accili.

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Plum, L., Lin, H., Dutia, R. et al. The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nat Med 15, 1195–1201 (2009). https://doi.org/10.1038/nm.2026

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