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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

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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 8

Female mice lacking TLR4 show increased obesity but are partially protected against high-fat diet–induced (HFD-induced) insulin resistance, and HFD does not induce inflammatory gene expression in fat and liver in these mice.

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Female mice lacking TLR4 show increased obesity but are partially protec...
(A) Body weights of WT and TLR4–/– mice on HFD or chow diet. (B) Lean and fat tissue weight as assessed by dual-energy x-ray absorptiometry at 26 weeks on HFD. (C) Cumulative food intake. Daily food intake was measured for 1 week after 22 weeks on diet. (D) Insulin tolerance test. Insulin (1 mU/g BW) was administered to mice after 36 weeks on diet. HFD induces inflammatory gene expression in fat (E) and liver (F) in WT but not TLR4-knockout mice. Data are expressed as mean ± SEM (n = 7–9). *P < 0.05, WT versus TLR4–/–; #P < 0.05 between groups as indicated.

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