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

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Zimmet, P., Alberti, K.G. & Shaw, J. Global and societal implications of the diabetes epidemic. Nature 414, 782–787 (2001).

  2. 2

    Spiegel, A., Nabel, E., Volkow, N., Landis, S. & Li, T.K. Obesity on the brain. Nat. Neurosci. 8, 552–553 (2005).

  3. 3

    Schwartz, M.W., Woods, S.C., Porte, D., Jr., Seeley, R.J. & Baskin, D.G. Central nervous system control of food intake. Nature 404, 661–671 (2000).

  4. 4

    Niswender, K.D. et al. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 413, 794–795 (2001).

  5. 5

    Niswender, K.D. et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52, 227–231 (2003).

  6. 6

    Bruning, J.C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).

  7. 7

    Burks, D.J. et al. IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 407, 377–382 (2000).

  8. 8

    Tang, E.D., Nunez, G., Barr, F.G. & Guan, K.L. Negative regulation of the forkhead transcription factor FKHR by Akt. J. Biol. Chem. 274, 16741–16746 (1999).

  9. 9

    Matsuzaki, H., Daitoku, H., Hatta, M., Tanaka, K. & Fukamizu, A. Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc. Natl. Acad. Sci. USA 100, 11285–11290 (2003).

  10. 10

    Aoki, M., Jiang, H. & Vogt, P.K. Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. Proc. Natl. Acad. Sci. USA 101, 13613–13617 (2004).

  11. 11

    Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423, 550–555 (2003).

  12. 12

    Furuyama, T., Kitayama, K., Yamashita, H. & Mori, N. Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem. J. 375, 365–371 (2003).

  13. 13

    Nakae, J. et al. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev. Cell 4, 119–129 (2003).

  14. 14

    Kitamura, T. et al. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J. Clin. Invest. 110, 1839–1847 (2002).

  15. 15

    Hwangbo, D.S., Gershman, B., Tu, M.P., Palmer, M. & Tatar, M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429, 562–566 (2004).

  16. 16

    Giannakou, M.E. et al. Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science 305, 361 (2004).

  17. 17

    Schwartz, M.W., Seeley, R.J., Campfield, L.A., Burn, P. & Baskin, D.G. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101–1106 (1996).

  18. 18

    Woods, S.C., Lotter, E.C., McKay, L.D. & Porte, D., Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979).

  19. 19

    Hall, R.K. et al. Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein-1 gene expression by insulin. The role of winged helix/forkhead proteins. J. Biol. Chem. 275, 30169–30175 (2000).

  20. 20

    Munzberg, H., Huo, L., Nillni, E.A., Hollenberg, A.N. & Bjorbaek, C. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology 144, 2121–2131 (2003).

  21. 21

    Xu, A.W. et al. PI3K integrates the action of insulin and leptin on hypothalamic neurons. J. Clin. Invest. 115, 951–958 (2005).

  22. 22

    Canick, J.A. et al. Localization of aromatase and 5 alpha-reductase to neuronal and non-neuronal cells in the fetal rat hypothalamus. Brain Res. 372, 277–282 (1986).

  23. 23

    Kim, M.S. et al. The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin. J. Clin. Invest. 105, 1005–1011 (2000).

  24. 24

    Morton, G.J. et al. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa(k)/fa(k)) rats. Endocrinology 144, 2016–2024 (2003).

  25. 25

    Furukawa, N. et al. Role of Rho-kinase in regulation of insulin action and glucose homeostasis. Cell Metab. 2, 119–129 (2005).

  26. 26

    Kim, M.S. et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat. Med. 10, 727–733 (2004).

  27. 27

    Wolak, M.L. et al. Comparative distribution of neuropeptide Y Y1 and Y5 receptors in the rat brain by using immunohistochemistry. J. Comp. Neurol. 464, 285–311 (2003).

Download references

Acknowledgements

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.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading