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AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus

Nature volume 428, pages 569–574 (2004)Cite this article

Abstract

Obesity is an epidemic in Western society, and causes rapidly accelerating rates of type 2 diabetes and cardiovascular disease. The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a ‘fuel gauge’ to monitor cellular energy status1. We investigated the potential role of AMPK in the hypothalamus in the regulation of food intake. Here we report that AMPK activity is inhibited in arcuate and paraventricular hypothalamus (PVH) by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin, high glucose and refeeding. A melanocortin receptor agonist, a potent anorexigen2, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen2, increases AMPK activity. Melanocortin receptor signalling is required for leptin and refeeding effects on AMPK in PVH. Dominant negative AMPK expression in the hypothalamus is sufficient to reduce food intake and body weight, whereas constitutively active AMPK increases both. Alterations of hypothalamic AMPK activity augment changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.

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Figure 1: Leptin, insulin, MT-II and glucose decrease α2AMPK activity in the hypothalamus.
Figure 2: Modulation of AMPK activity in the hypothalamus is sufficient to alter body weight and food intake.
Figure 3: Effects of leptin are impaired with CA-AMPK in the hypothalamus.
Figure 4: Proposed model for role of AMPK in anorexigenic signalling in the hypothalamus.

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Acknowledgements

We thank D. Carling for reagents and advice, J. K. Elmquist and B. B. Lowell for discussions and providing MC4R-KO mice, and C. J. Aschkenasi, C.-Y. Zhang, O. Boss, J. Yu and N. Balthasar for MC4R-KO mice. This work was supported by NIH grants (B.B.K. and M.J.B.), an EASD-ADA and Bettencourt-Schueller Foundation Fellowship (T.A.), AMPDIAMET (P.F.) and the American Diabetes Association (B.B.K. and Y.B.K.).

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Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02215, USA

    Yasuhiko Minokoshi, Thierry Alquier, Noboru Furukawa, Young-Bum Kim, Anna Lee, Bingzhong Xue, Bettina J. Stuck & Barbara B. Kahn

  2. Howard Hughes Medical Institute, The Cox Institute, University of Pennsylvania Medical School, Philadelphia, Pennsylvania, 19104, USA

    James Mu & Morris J. Birnbaum

  3. Unit 465 INSERM, Centre de Recherches Biomedicales des Cordeliers, 75270, Cedex 6, Paris, France

    Fabienne Foufelle & Pascal Ferré

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  1. Yasuhiko Minokoshi
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Correspondence to Barbara B. Kahn.

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Supplementary information

Supplementary Methods (PDF 160 kb)

Supplementary Figure 1

mRNA levels of neuropeptides in dissected hypothalamic samples. (PDF 65 kb)

Supplementary Figure 2

Protein expression of α2 subunit of AMPK and STAT3 in ARH and VMH/DMH. (PDF 73 kb)

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Minokoshi, Y., Alquier, T., Furukawa, N. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004). https://doi.org/10.1038/nature02440

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