Nature Neuroscience 9, 901 - 906 (2006)
Published online: 18 June 2006; | doi:10.1038/nn1731
Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasisMin-Seon Kim1, 6, Youngmi K Pak2, 6, Pil-Geum Jang2, 6, Cherl Namkoong2, Yon-Sik Choi2, Jong-Chul Won1, Kyung-Sup Kim3, Seung-Whan Kim1, 2, Hyo-Soo Kim4, Joong-Yeol Park1, Young-Bum Kim5
& Ki-Up Lee11
Department of Internal Medicine, University of Ulsan College of Medicine, 138-736 Pungnap-dong, Songpa-ku, Seoul 138-736, Korea. 2
Asan Institute for Life Sciences, University of Ulsan College of Medicine, 138-736 Pungnap-dong, Songpa-ku, Seoul 138-736, Korea. 3
Department of Biochemistry and Molecular Biology, Yonsei University School of Medicine, 134 Shinchon-dong, Seodaemoon-ku, Seoul 120-752, Korea. 4
Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-ku, Seoul 110-744, Korea. 5
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA. 6
These authors contributed equally to this work.
Correspondence should be addressed to Ki-Up Lee kulee@amc.seoul.kr Insulin signaling in the hypothalamus plays a role in maintaining body weight. Studies suggest that the forkhead transcription factor Foxo1 is an important mediator of insulin signaling in peripheral tissues. Here we demonstrate that in normal mice, hypothalamic Foxo1 expression is reduced by the anorexigenic hormones insulin and leptin. These hormones' effects on feeding are inhibited when hypothalamic Foxo1 is activated, establishing a new signaling pathway through which insulin and leptin regulate food intake in hypothalamic neurons. Moreover, activation of Foxo1 in the hypothalamus increases food intake and body weight, whereas inhibition of Foxo1 decreases both. Foxo1 stimulates the transcription of the orexigenic neuropeptide Y and Agouti-related protein through the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, but suppresses the transcription of anorexigenic proopiomelanocortin by antagonizing the activity of signal transducer–activated transcript-3 (STAT3). Our data suggest that hypothalamic Foxo1 is an important regulator of food intake and energy balance.
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