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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 Article has an altmetric score of 4

Brain fatty acid synthase activates PPARα to maintain energy homeostasis

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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 2

FAS does not play a major role in pancreatic β cell function.

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FAS does not play a major role in pancreatic β cell function.
(A) Glucos...
(A) Glucose (1 g/kg, 10% D-glucose) tolerance tests (i.p.) in 4-month-old WT and FASKO mice (n = 8). (B) Serum glucose and (C) insulin concentrations immediately before (time 0) and 30 minutes after the glucose load (n = 8). (D) Isolated islets from WT and FASKO mice cultured with 3 mM and 20 mM glucose (n = 7). (E) Insulin content from whole pancreas and (F) isolated islets (n = 7). (G) Representative pancreatic sections immunostained with antibodies against insulin (green) and a mixture of anti-glucagon, anti-pancreatic polypeptide, and anti-somatostatin antibodies (red) in WT and FASKO mice (n = 3). Original magnification, ×20. (H) Islet β cell mass (n = 4). (I) Gene expression by quantitative RT-PCR for glucokinase (Gck), Glut2, and Pdx-1 in isolated islets from WT and FASKO mice (n = 5). All bars represent mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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