Article abstract
Nature Medicine 15, 1195 - 1201 (2009)
Published online: 20 September 2009 | doi:10.1038/nm.2026
The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake
Leona Plum1,5, Hua V Lin1, Roxanne Dutia1, Jun Tanaka1, Kumiko S Aizawa1, Michihiro Matsumoto1,2, Andrea J Kim1, Niamh X Cawley3, Ji-Hye Paik4, Y Peng Loh3, Ronald A DePinho4, Sharon L Wardlaw1 & Domenico Accili1
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 
-melanocyte–stimulating hormone (-Msh) and carboxy-cleaved 
-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.
- Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York, USA.
- Department of Clinical Pharmacology, International Medical Center of Japan, Tokyo, Japan.
- Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA.
- Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine, and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
- Present address: Department of Clinical Research, Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany.
Correspondence to: Domenico Accili1 e-mail: da230@columbia.edu
