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Papers In Press, published online ahead of print April 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800379-JLR200

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Journal of Lipid Research, Vol. 50, 630-640, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Inactivation of hypothalamic FAS protects mice from diet-induced obesity and inflammation^*,

Manu V. Chakravarthy^*, Yimin Zhu^*, Li Yin^*, Trey Coleman^*, Kirk L. Pappan, Connie A. Marshall, Michael L. McDaniel and Clay F. Semenkovich^1,*,

^* Department of Medicine, Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine in St. Louis, MO 63110
Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, MO 63110
Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, MO 63110

^* This work was supported by the American Diabetes Association (Junior Faculty Award 1-07-JF-12 to MVC and a Mentor-Based Postdoctoral Fellowship Award), National Institutes of Health grants DK076729 and P50 HL083762, and the Clinical Nutrition Research Unit (DK56341) and Diabetes Research and Training Center (DK20579).

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two tables and one figure.

Published, JLR Papers in Press, November 22, 2008.

¹ To whom correspondence should be addressed. e-mail: csemenko{at}wustl.edu

Obesity promotes insulin resistance and chronic inflammation. Disrupting any of several distinct steps in lipid synthesis decreases adiposity, but it is unclear if this approach coordinately corrects the environment that propagates metabolic disease. We tested the hypothesis that inactivation of FAS in the hypothalamus prevents diet-induced obesity and systemic inflammation. Ten weeks of high-fat feeding to mice with inactivation of FAS (FASKO) limited to the hypothalamus and pancreatic β cells protected them from diet-induced obesity. Though high-fat fed FASKO mice had no β-cell phenotype, they were hypophagic and hypermetabolic, and they had increased insulin sensitivity at the liver but not the periphery as demonstrated by hyperinsulinemic-euglycemic clamps, and biochemically by increased phosphorylated Akt, glycogen synthase kinase-3beta, and FOXO1 compared with wild-type mice. High-fat fed FASKO mice had decreased excretion of urinary isoprostanes, suggesting less oxidative stress and blunted tumor necrosis factor alpha (TNF) and interleukin-6 (IL-6) responses to endotoxin, suggesting less systemic inflammation. Pair-feeding studies demonstrated that these beneficial effects were dependent on central FAS disruption and not merely a consequence of decreased adiposity. Thus, inducing central FAS deficiency may be a valuable integrative strategy for treating several components of the metabolic syndrome, in part by correcting hepatic insulin resistance and suppressing inflammation.

Supplementary key words metabolic syndrome • insulin resistance • type 2 diabetes mellitus

Abbreviations: HFD, high-fat diet; IL-6, interleukin-6; FASKO, fatty acid synthase knockout; Ppar, peroxisome-proliferator-activated receptor; TNF, tumor necrosis factor alpha

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