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J. Neurosci. 29 (2): 359-370

Copyright © 2009 by the Society for Neuroscience.

Cellular/Molecular

Saturated Fatty Acids Produce an Inflammatory Response Predominantly through the Activation of TLR4 Signaling in Hypothalamus: Implications for the Pathogenesis of Obesity

Marciane Milanski,1 Giovanna Degasperi,1 Andressa Coope,1 Joseane Morari,1 Raphael Denis,1 Dennys E. Cintra,1 Daniela M. L. Tsukumo,1 Gabriel Anhe,3 Maria E. Amaral,1 Hilton K. Takahashi,3 Rui Curi,3 Helena C. Oliveira,2 José B. C. Carvalheira,1 Silvana Bordin,3 Mário J. Saad,1 , and Lício A. Velloso1

Departments of 1Internal Medicine and 2Physiology and Biophysics, Faculty of Medical Sciences, University of Campinas, 13083-970 Campinas, São Paulo, Brazil, and 3Department of Physiology and Biophysics, University of São Paulo, 05508-900 São Paulo, Brazil

Correspondence should be addressed to Lício A. Velloso, Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, 13083-970 Campinas, São Paulo, Brazil. Email: lavelloso{at}fcm.unicamp.br

Abstract: In animal models of diet-induced obesity, the activation of an inflammatory response in the hypothalamus produces molecular and functional resistance to the anorexigenic hormones insulin and leptin. The primary events triggered by dietary fats that ultimately lead to hypothalamic cytokine expression and inflammatory signaling are unknown. Here, we test the hypothesis that dietary fats act through the activation of toll-like receptors 2/4 and endoplasmic reticulum stress to induce cytokine expression in the hypothalamus of rodents. According to our results, long-chain saturated fatty acids activate predominantly toll-like receptor 4 signaling, which determines not only the induction of local cytokine expression but also promotes endoplasmic reticulum stress. Rats fed on a monounsaturated fat-rich diet do not develop hypothalamic leptin resistance, whereas toll-like receptor 4 loss-of-function mutation and immunopharmacological inhibition of toll-like receptor 4 protects mice from diet-induced obesity. Thus, toll-like receptor 4 acts as a predominant molecular target for saturated fatty acids in the hypothalamus, triggering the intracellular signaling network that induces an inflammatory response, and determines the resistance to anorexigenic signals.

Key Words: obesity • inflammation • hypothalamus • cytokine • nutrition • feeding

Received for publication June 17, 2008. Revision received Nov. 3, 2008. Accepted for publication Nov. 20, 2008.

Correspondence should be addressed to Lício A. Velloso, Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, 13083-970 Campinas, São Paulo, Brazil. Email: lavelloso{at}fcm.unicamp.br

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