Brain fatty acid synthase activates PPARα to maintain energy homeostasis
Manu V. Chakravarthy, … , M. Daniel Lane, Clay F. Semenkovich
Manu V. Chakravarthy, … , M. Daniel Lane, Clay F. Semenkovich
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2539-2552. https://doi.org/10.1172/JCI31183.
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Research Article Metabolism

Brain fatty acid synthase activates PPARα to maintain energy homeostasis

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.

Authors

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

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Figure 7

FASKO mice have impaired hypothalamic PPARα signaling.

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FASKO mice have impaired hypothalamic PPARα signaling. (A) Expression of...
(A) Expression of PPARα and its target genes (ACO, CPT-1, and MCD) in hypothalamus by quantitative RT-PCR in freely fed controls (WT-Ctrl), FASKO mice, and WT mice pair-fed with FASKO mice (WT-PF). Bars represent mean ± SEM of 8–10 animals per genotype. *P < 0.05 compared with WT-Ctrl. #P < 0.05 compared with freely fed FASKO mice. (B–D) Dose-dependent effect of i.c.v. administration of Wy14,643 on food/water intake and body weight. Eight-week-old male WT mice weighing approximately 25 g with chronically implanted i.c.v. cannulae received either vehicle (Veh; 20% DMSO in artificial cerebrospinal fluid) or the indicated doses of Wy14,643 (Wy) (n = 4 for each dose) after a 23.5-hour fast. The initial i.c.v. dose (40 μg) in a 25-gram mouse approximates the i.p. dose (40 mg/kg) known to induce anorexia in mice (37). Doses were titrated until no systemic aversive effects, including changes in food and water intake or body weight, were noted 24 hours after refeeding following treatment. Data represent mean ± SEM. *P < 0.05 compared with vehicle-treated animals.