Saturated Fatty Acids Produce an Inflammatory Response Predominantly through the Activation of TLR4 Signaling in Hypothalamus: Implications for the Pathogenesis of Obesity
Contribuinte(s) |
UNIVERSIDADE DE SÃO PAULO |
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Data(s) |
20/10/2012
20/10/2012
2009
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Resumo |
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. Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) FAPESP Fundacao de Amparo a Pesquisa do Estado de Sao Paulo Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) CNPq Conselho Nacional de Desenvolvimento cientifico e Tecnologico |
Identificador |
JOURNAL OF NEUROSCIENCE, v.29, n.2, p.359-370, 2009 0270-6474 http://producao.usp.br/handle/BDPI/27915 10.1523/JNEUROSCI.2760-08.2009 |
Idioma(s) |
eng |
Publicador |
SOC NEUROSCIENCE |
Relação |
Journal of Neuroscience |
Direitos |
restrictedAccess Copyright SOC NEUROSCIENCE |
Palavras-Chave | #obesity #inflammation #hypothalamus #cytokine #nutrition #feeding #ENDOPLASMIC-RETICULUM STRESS #DIET-INDUCED OBESITY #CORONARY HEART-DISEASE #NF-KAPPA-B #INSULIN-RESISTANCE #GLUCOSE-HOMEOSTASIS #LEPTIN RESISTANCE #INNATE IMMUNITY #RISK-FACTORS #ER STRESS #Neurosciences |
Tipo |
article original article publishedVersion |