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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We thank K.L. Guan (University of Michigan) for providing Foxo1 and Foxo1-3A expression plasmids and J.K. Elmquist (University of Texas Southwestern Medical Center) for critical reading and suggestions. This study was supported by grants from the Korean Ministry of Health & Welfare (A05-0513, 03-PJ1-PG1-CH05-0005), the Korean Ministry of Science and Technology (National Research Laboratory grant M1040000000804J000000810, 21C Frontier Functional Proteomics Project FPR05C2-450), the Korean Research Foundation (E00176), the Asan Institute for Life Science (04-326) and the American Diabetes Association (7-02-JF-26 and 7-05-PPG-02 to Y.-B.K.).
The authors declare no competing financial interests.
Foxo1 expression in hypothalamic neurons. (PDF 138 kb)
Verification of the correct injection of adenovirus into the hypothalamus. (PDF 24 kb)
Effect of wild-type (WT)-Foxo1 expression in the bilateral ARC on food intake. (PDF 14 kb)
Inhibition of Foxo1 mRNA (a, b) and protein (c, d) expression by Foxo1 siRNAs in C2C12 cells. (PDF 50 kb)
Increased intra-nuclear phospho-Foxo1 expression following treatment with insulin or leptin. (PDF 25 kb)
Foxo1 protein expression in various hypothalamic nuclei. (PDF 31 kb)
Mismatched siRNA controls did not affect Foxo1 protein expression. (PDF 39 kb)
Transfection efficacy of FITC-labeled siRNA. (PDF 386 kb)
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Kim, M., Pak, Y., Jang, P. et al. Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat Neurosci 9, 901–906 (2006) doi:10.1038/nn1731
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