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 5

Lipid infusion activates TLR4 signaling in adipose tissue in vivo.

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Lipid infusion activates TLR4 signaling in adipose tissue in vivo. (A) S...
(A) Schematic diagram of lipid infusion and inflammatory signaling studies. (B) Lipid infusion increases NF-κB DNA binding in adipose tissue of WT but not TLR4–/– mice. Mice were fasted overnight and infused with lipid (coupled with heparin) for 8 hours. EMSA was conducted to examine the NF-κB DNA binding activity. (C) Lipid infusion increases NF-κB DNA binding to the IL-6 promoter. ChIP assays were conducted to quantify NF-κB DNA binding to the IL-6 promoter. SYBR Green quantitative PCR was used to measure the immunoprecipitated DNA (n = 3; *P < 0.01). (D–F) Lipid infusion increases TNF-α, IL-6, and MCP-1 mRNA expression in adipose tissue of WT but not TLR4–/– mice (n = 4; *P < 0.05). Data are expressed as mean ± SEM.