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

被引:129
作者
Plum, Leona [1 ,2 ]
Lin, Hua V. [1 ,2 ]
Dutia, Roxanne [1 ,2 ]
Tanaka, Jun [1 ,2 ]
Aizawa, Kumiko S. [1 ,2 ]
Matsumoto, Michihiro [1 ,2 ,3 ]
Kim, Andrea J. [1 ,2 ]
Cawley, Niamh X. [4 ]
Paik, Ji-Hye [5 ,6 ,7 ,8 ]
Loh, Y. Peng [4 ]
DePinho, Ronald A. [5 ,6 ,7 ,8 ]
Wardlaw, Sharon L. [1 ,2 ]
Accili, Domenico [1 ,2 ]
机构
[1] Columbia Univ, Naomi Berrie Diabet Ctr, New York, NY 10027 USA
[2] Columbia Univ, Dept Med, New York, NY USA
[3] Int Med Ctr Japan, Dept Clin Pharmacol, Tokyo, Japan
[4] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, Cellular Neurobiol Sect, Bethesda, MD USA
[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[7] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA
[8] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Genet, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
PROTHYROTROPIN-RELEASING HORMONE; PROHORMONE CONVERTASES; BETA-ENDORPHIN; BODY-WEIGHT; CPE(FAT)/CPE(FAT) MICE; STIMULATING HORMONE; ENERGY HOMEOSTASIS; LEPTIN; PEPTIDE; INSULIN;
D O I
10.1038/nm.2026
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 alpha-melanocyt-estimulating hormone (alpha-Msh) and carboxy-cleaved beta-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.
引用
收藏
页码:1195 / U125
页数:8
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