Regulation of adaptive behaviour during fasting by hypothalamic Foxa2

Jose P. Silva, Ferdinand Von Meyenn, Jessica Howell, Bernard Thorens, Christian Wolfrum, Markus Stoffel

Research output: Contribution to journalArticle

51 Citations (Scopus)

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). 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 signalling, 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/+;Foxa2T156A flox/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.

Original languageEnglish
Pages (from-to)646-650
Number of pages5
JournalNature
Volume462
Issue number7273
DOIs
StatePublished - Dec 3 2009
Externally publishedYes

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Psychological Adaptation
Fasting
Lateral Hypothalamic Area
Obese Mice
Insulin
Forkhead Transcription Factors
Brain
Arousal
Neuropeptides
Insulin Resistance
Homeostasis
Eating
Fats
Genotype
melanin-concentrating hormone
Neurons
Glucose
Food
Mutation

ASJC Scopus subject areas

  • General

Cite this

Silva, J. P., Von Meyenn, F., Howell, J., Thorens, B., Wolfrum, C., & Stoffel, M. (2009). Regulation of adaptive behaviour during fasting by hypothalamic Foxa2. Nature, 462(7273), 646-650. https://doi.org/10.1038/nature08589

Regulation of adaptive behaviour during fasting by hypothalamic Foxa2. / Silva, Jose P.; Von Meyenn, Ferdinand; Howell, Jessica; Thorens, Bernard; Wolfrum, Christian; Stoffel, Markus.

In: Nature, Vol. 462, No. 7273, 03.12.2009, p. 646-650.

Research output: Contribution to journalArticle

Silva, JP, Von Meyenn, F, Howell, J, Thorens, B, Wolfrum, C & Stoffel, M 2009, 'Regulation of adaptive behaviour during fasting by hypothalamic Foxa2', Nature, vol. 462, no. 7273, pp. 646-650. https://doi.org/10.1038/nature08589
Silva JP, Von Meyenn F, Howell J, Thorens B, Wolfrum C, Stoffel M. Regulation of adaptive behaviour during fasting by hypothalamic Foxa2. Nature. 2009 Dec 3;462(7273):646-650. https://doi.org/10.1038/nature08589
Silva, Jose P. ; Von Meyenn, Ferdinand ; Howell, Jessica ; Thorens, Bernard ; Wolfrum, Christian ; Stoffel, Markus. / Regulation of adaptive behaviour during fasting by hypothalamic Foxa2. In: Nature. 2009 ; Vol. 462, No. 7273. pp. 646-650.
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