TLR4 links innate immunity and fatty acid–induced insulin resistance
Hang Shi, … , Huali Yin, Jeffrey S. Flier
Hang Shi, … , Huali Yin, Jeffrey S. Flier
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):3015-3025. https://doi.org/10.1172/JCI28898.
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Research Article Metabolism

TLR4 links innate immunity and fatty acid–induced insulin resistance

Abstract

TLR4 is the receptor for LPS and plays a critical role in innate immunity. Stimulation of TLR4 activates proinflammatory pathways and induces cytokine expression in a variety of cell types. Inflammatory pathways are activated in tissues of obese animals and humans and play an important role in obesity-associated insulin resistance. Here we show that nutritional fatty acids, whose circulating levels are often increased in obesity, activate TLR4 signaling in adipocytes and macrophages and that the capacity of fatty acids to induce inflammatory signaling in adipose cells or tissue and macrophages is blunted in the absence of TLR4. Moreover, mice lacking TLR4 are substantially protected from the ability of systemic lipid infusion to (a) suppress insulin signaling in muscle and (b) reduce insulin-mediated changes in systemic glucose metabolism. Finally, female C57BL/6 mice lacking TLR4 have increased obesity but are partially protected against high fat diet–induced insulin resistance, possibly due to reduced inflammatory gene expression in liver and fat. Taken together, these data suggest that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.

Authors

Hang Shi, Maia V. Kokoeva, Karen Inouye, Iphigenia Tzameli, Huali Yin, Jeffrey S. Flier

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Figure 1

FFAs activate TLR4 signaling.

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FFAs activate TLR4 signaling. (A) FFAs activate TLR4 signaling in transf...
(A) FFAs activate TLR4 signaling in transfected 293T cells (n = 6; *P < 0.01). 293T cells were transiently transfected with TLR4/MD-2 expression vectors, with or without dominant negative MyD88 (MyD88-DN), and an NF-κB luciferase reporter and were then treated with a 200 μM oleate/palmitate mixture or 100 ng/ml LPS as a positive control. (B) FFAs cause IκBα degradation and JNK phosphorylation in WT but not TLR4-deficient macrophages. Peritoneal macrophages were isolated and precultured for 4 days before treatment. Cells were treated with 500 μM palmitate over the time course indicated. NS, nonspecific. (C and D) FFAs induce TNF-α and IL-6 mRNA in peritoneal macrophages in WT but not TLR4–/– mice (n = 4; *P < 0.01). Peritoneal macrophages were treated with 200 μM FFA mixture for 8 hours. Real-time RT-PCR was used to measure mRNA levels. Data are expressed as mean ± SEM.