Does a Fatty Diet Take a Toll on Leptin Signaling?

Science Signaling  20 Jan 2009:
Vol. 2, Issue 54, pp. ec20
DOI: 10.1126/scisignal.254ec20

Animal models of obesity indicate that the consumption of a high-fat diet can lead to an inflammatory response in the hypothalamus and thereby to insulin and leptin resistance and dysregulated energy balance. Noting that cytokine production in response to activation of Toll-like receptor (TLR) signaling and of the endoplasmic reticulum (ER) stress response has been implicated in development of insulin resistance in peripheral tissues, Milanski et al. investigated the mechanisms whereby high-fat diet elicits an inflammatory hypothalamic response. Rats fed a diet rich in saturated fat (HF diet) showed increased abundance of various cytokines in the hypothalamus compared with rats fed normal chow. Intracerebroventricular administration of different fatty acids indicated that long-chain saturated fatty acids elicited the most pronounced hypothalamic inflammatory response. Moreover, whereas HF diet promoted leptin resistance, consumption of a calorically equivalent diet high in unsaturated fatty acids did not. Administration of the long-chain saturated fatty acid arachidic acid elicited association of MyD88 with TLR2 and TLR4 (indicative of their increased activation) and phosphorylation of proteins implicated in the ER stress response; moreover, hypothalamic association of MyD88 with TLR2 and TLR4 was enhanced in rats fed a HF diet. Analysis of the effects of inhibitory antibodies directed against TLR2 and TLR4, as well as that of a protein chaperone, indicated that TLR4 activation was primary; ER stress was secondary and mediated part of the response. Mice with a TLR4 loss-of-function mutation showed a smaller increase in body mass with a HF diet than did control mice; indeed, intraperitoneal or intracerebroventricular administration of the TLR4-inhibitory antibody inhibited diet-induced weight gain. The authors thus propose that activation of TLR4 by saturated fatty acids plays an important role in the hypothalamic response to HF diet, leptin resistance, and the pathogenesis of obesity.

M. Milanski, G. Degasperi, A. Coope, J. Morari, R. Denis, D. E. Cintra, D. M. L. Tsukumo, G. Anhe, M. E. Amaral, H. K. Takahashi, R. Curi, H. C. Oliveira, J. B. C. Carvalheira, S. Bordin, M. J. Saad, L. A. Velloso, Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: Implications for the pathogenesis of obesity. J. Neurosci. 29, 359–370 (2009). [Abstract] [Full Text]