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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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 4

FFAs cause inflammatory response via TLR4 in adipocytes.

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FFAs cause inflammatory response via TLR4 in adipocytes. (A–C) Generatio...
(A–C) Generation of an adipocyte model with specific TLR4 knockdown. 3T3-L1 preadipocytes were infected with retroviral short hairpin RNA interference (shRNAi) to knock down TLR4 (TLR4-KD), and cells were selected and then differentiated into adipocytes. TLR4 mRNA (A) and protein (B) and TLR2 mRNA (C) levels were evaluated by real-time RT-PCR and immunoblotting. Data are expressed as mean ± SEM; n = 6; *P < 0.05. (D and E) FFAs stimulate IL-6 and TNF-α mRNA expression in 3T3-L1 adipocytes via TLR4. TLR4-knockdown and scramble control adipocytes were treated with 400 μM FFA (palmitate and oleate mixture) or 100 ng/ml LPS for 12 hours. Real-time RT-PCR was conducted to measure the mRNA levels. n = 4; *P < 0.05. (F and G) FFAs stimulate TNF-α and IL-6 mRNA in WT but not in TLR4–/– adipocytes (n = 4; *P < 0.05). (H and I) FFAs stimulate TNF-α and IL-6 protein secretion in WT but not in TLR4–/– adipocytes (n = 4; *P < 0.05). Mouse adipocytes were isolated and precultured for 6 hours and then were treated with 400 μM FFA mixture for 16 hours. Real-time RT-PCR was used to measure mRNA levels. Data are expressed as mean ± SEM.