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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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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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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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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DOI: https://doi.org/10.1038/nm.2026
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