Nature Medicine
- 12, 534 - 540 (2006)
Published online: 9 April 2006; | doi:10.1038/nm1392
Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intakeTadahiro Kitamura1, 5, Yun Feng2, 3, 5, Yukari Ido Kitamura1, Streamson C Chua Jr3, Allison W Xu4, Gregory S Barsh4, Luciano Rossetti2, 3 & Domenico Accili11
Department of Medicine, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, New York 10032, USA. 2
Departments of Medicine and Molecular Pharmacology, 1300 Morris Park Avenue, Bronx, New York 10461, USA. 3
Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. 4
Departments of Genetics and Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA. 5
These authors contributed equally to this work.
Correspondence should be addressed to Domenico Accili da230@columbia.edu Leptin controls food intake by regulating the transcription of key neuropeptides in the hypothalamus. The mechanism by which leptin regulates gene expression is unclear, however. Here we show that delivery of adenovirus encoding a constitutively nuclear mutant FoxO1, a transcription factor known to control liver metabolism and pancreatic beta-cell function, to the hypothalamic arcuate nucleus of rodents results in a loss of the ability of leptin to curtail food intake and suppress expression of Agrp. Conversely, a transactivation-deficient FoxO1 mutant prevents induction of Agrp by fasting. We also find that FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of Agrp and Pomc through transcriptional squelching. FoxO1 promotes opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc. Thus, FoxO1 represents a shared component of pathways integrating food intake and peripheral metabolism.
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