Brain fatty acid synthase activates PPAR? to maintain energy homeostasis

Manu V. Chakravarthy, Yimin Zhu, Miguel López, Li Yin, David F. Wozniak, Trey Coleman, Zhiyuan Hu, Michael J Wolfgang, Antonio Vidal-Puig, M. Daniel Lane, Clay F. Semenkovich

Research output: Contribution to journalArticle

Abstract

Central nervous system control of energy balance affects susceptibility to obesity and diabetes, but how fatty acids, malonyl-CoA, and other metabolites act at this site to alter metabolism is poorly understood. Pharmacological inhibition of fatty acid synthase (FAS), rate limiting for de novo lipogenesis, decreases appetite independently of leptin but also promotes weight loss through activities unrelated to FAS inhibition. Here we report that the conditional genetic inactivation of FAS in pancreatic β cells and hypothalamus produced lean, hypophagic mice with increased physical activity and impaired hypothalamic PPARα signaling. Administration of a PPARα agonist into the hypothalamus increased PPARα target genes and normalized food intake. Inactivation of β cell FAS enzyme activity had no effect on islet function in culture or in vivo. These results suggest a critical role for brain FAS in the regulation of not only feeding, but also physical activity, effects that appear to be mediated through the provision of ligands generated by FAS to PPARα. Thus, 2 diametrically opposed proteins, FAS (induced by feeding) and PPARα (induced by starvation), unexpectedly form an integrative sensory module in the central nervous system to orchestrate energy balance.

Original languageEnglish (US)
Pages (from-to)2539-2552
Number of pages14
JournalJournal of Clinical Investigation
Volume117
Issue number9
DOIs
StatePublished - Sep 4 2007

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Fatty Acid Synthases
Peroxisome Proliferator-Activated Receptors
Homeostasis
Brain
Hypothalamus
Central Nervous System
Malonyl Coenzyme A
Lipogenesis
Appetite
Starvation
Leptin
Weight Loss
Fatty Acids
Obesity
Eating
Pharmacology
Ligands
Enzymes
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chakravarthy, M. V., Zhu, Y., López, M., Yin, L., Wozniak, D. F., Coleman, T., ... Semenkovich, C. F. (2007). Brain fatty acid synthase activates PPAR? to maintain energy homeostasis. Journal of Clinical Investigation, 117(9), 2539-2552. https://doi.org/10.1172/JCI31183

Brain fatty acid synthase activates PPAR? to maintain energy homeostasis. / Chakravarthy, Manu V.; Zhu, Yimin; López, Miguel; Yin, Li; Wozniak, David F.; Coleman, Trey; Hu, Zhiyuan; Wolfgang, Michael J; Vidal-Puig, Antonio; Lane, M. Daniel; Semenkovich, Clay F.

In: Journal of Clinical Investigation, Vol. 117, No. 9, 04.09.2007, p. 2539-2552.

Research output: Contribution to journalArticle

Chakravarthy, MV, Zhu, Y, López, M, Yin, L, Wozniak, DF, Coleman, T, Hu, Z, Wolfgang, MJ, Vidal-Puig, A, Lane, MD & Semenkovich, CF 2007, 'Brain fatty acid synthase activates PPAR? to maintain energy homeostasis', Journal of Clinical Investigation, vol. 117, no. 9, pp. 2539-2552. https://doi.org/10.1172/JCI31183
Chakravarthy MV, Zhu Y, López M, Yin L, Wozniak DF, Coleman T et al. Brain fatty acid synthase activates PPAR? to maintain energy homeostasis. Journal of Clinical Investigation. 2007 Sep 4;117(9):2539-2552. https://doi.org/10.1172/JCI31183
Chakravarthy, Manu V. ; Zhu, Yimin ; López, Miguel ; Yin, Li ; Wozniak, David F. ; Coleman, Trey ; Hu, Zhiyuan ; Wolfgang, Michael J ; Vidal-Puig, Antonio ; Lane, M. Daniel ; Semenkovich, Clay F. / Brain fatty acid synthase activates PPAR? to maintain energy homeostasis. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 9. pp. 2539-2552.
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