Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis


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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Figure 1: Hypothalamic Foxo1 expression affects food intake and body weight.
Figure 2: Inhibitory effects of insulin and leptin on hypothalamic Foxo1 expression.
Figure 3: Foxo1 binds to the Npy promoter.
Figure 4: Foxo1 stimulates Npy transcriptional activity.
Figure 5: Effect of Foxo1 on transcriptional activity of Agrp and Pomc.


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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.).

Author information

M.-S.K., Y.-K.P. and K.-U.L. designed the research and wrote the paper; P.-G.J., C.N., Y.-S.C., J.-C.W., K.-S.K. and H.-S.K. performed the research; S.-W.K., J.-Y.P. and Y.-B.K. discussed the data.

Note: Supplementary information is available on the Nature Neuroscience website.

Correspondence to Ki-Up Lee.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Foxo1 expression in hypothalamic neurons. (PDF 138 kb)

Supplementary Fig. 2

Verification of the correct injection of adenovirus into the hypothalamus. (PDF 24 kb)

Supplementary Fig. 3

Effect of wild-type (WT)-Foxo1 expression in the bilateral ARC on food intake. (PDF 14 kb)

Supplementary Fig. 4

Inhibition of Foxo1 mRNA (a, b) and protein (c, d) expression by Foxo1 siRNAs in C2C12 cells. (PDF 50 kb)

Supplementary Fig. 5

Increased intra-nuclear phospho-Foxo1 expression following treatment with insulin or leptin. (PDF 25 kb)

Supplementary Fig. 6

Foxo1 protein expression in various hypothalamic nuclei. (PDF 31 kb)

Supplementary Fig. 7

Mismatched siRNA controls did not affect Foxo1 protein expression. (PDF 39 kb)

Supplementary Fig. 8

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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