Regulation of adaptive behaviour during fasting by hypothalamic Foxa2

Abstract

The lateral hypothalamic area is considered the classic ‘feeding centre’, regulating food intake, arousal and motivated behaviour through the actions of orexin and melanin-concentrating hormone (MCH)1,2,3. These neuropeptides are inhibited in response to feeding-related signals and are released during fasting. However, the molecular mechanisms that regulate and integrate these signals remain poorly understood. Here we show that the forkhead box transcription factor Foxa2, a downstream target of insulin signalling4,5,6, regulates the expression of orexin and MCH. During fasting, Foxa2 binds to MCH and orexin promoters and stimulates their expression. In fed and in hyperinsulinemic obese mice, insulin signalling leads to nuclear exclusion of Foxa2 and reduced expression of MCH and orexin. Constitutive activation of Foxa2 in the brain (Nes-Cre/+;Foxa2T156Aflox/flox genotype) results in increased neuronal MCH and orexin expression and increased food consumption, metabolism and insulin sensitivity. Spontaneous physical activity of these animals in the fed state is significantly increased and is similar to that in fasted mice. Conditional activation of Foxa2 through the T156A mutation expression in the brain of obese mice also resulted in improved glucose homeostasis, decreased fat and increased lean body mass. Our results demonstrate that Foxa2 can act as a metabolic sensor in neurons of the lateral hypothalamic area to integrate metabolic signals, adaptive behaviour and physiological responses.

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Figure 1: Foxa2 is co-expressed with MCH and orexin in the lateral hypothalamus and its subcellular localization is regulated by insulin.
Figure 2: Permanent inactivation of Foxa2 and reduced expression of MCH and orexin in hypothalamus of hyperinsulinemic, obese mice.
Figure 3: Constitutive nuclear Foxa2T156A activates Pmch and Hcrt expression in fed mice.
Figure 4: Metabolic measurements in HFD, brain-specific Foxa2T156A mice.

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Acknowledgements

This study was supported by grants from SystemsX and the Swiss National Science Foundation (LiverX grant). We would like to thank S. Metref for technical support and expertise.

Author Contributions J.P.S.: project design, characterization of mice, transcriptional activation, preparation of manuscript; F.v.M.: immunohistochemistry, nuclear/cytosolic immunoblot analysis, characterization of mice; J.H.: nuclear/cytosolic immunoblot analysis; B.T.: hypothalamic adenovirus injections; C.W.: generation and characterization of mice; M.S.: project design, preparation of manuscript.

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Correspondence to Markus Stoffel.

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Silva, J., von Meyenn, F., Howell, J. et al. Regulation of adaptive behaviour during fasting by hypothalamic Foxa2 . Nature 462, 646–650 (2009). https://doi.org/10.1038/nature08589

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