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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.
Nonstandard abbreviations used: ChIP, chromatin immunoprecipitacion; DIO, diet-induced obese; IRS-1, insulin receptor substrate-1; MCP-1, monocyte chemoattractant protein-1; MyD88, myeloid differentiation factor 88.
Introduction
Obesity is the most important identified factor contributing to insulin resistance (1, 2). The physiological mechanisms linking obesity to insulin resistance have received intense investigation and include altered production of various adipocyte-derived molecules, among which are the adipokines adiponectin and resistin, proinflammatory cytokines such as TNF-α and IL-6, RBP4, and FFAs themselves (1-7). It is increasingly recognized that obesity is characterized by chronic activation of inflammatory pathways and that inflammatory signaling pathways in obesity are causally linked to insulin resistance (1, 2, 7). However, the fundamental mechanisms responsible for activating inflammatory pathways in obesity are poorly understood. FFAs, levels of which are elevated in obesity, due to increased release from expanded adipose tissue, have been hypothesized to cause insulin resistance. Indeed, FFA infusion in vivo has been shown to impair the ability of insulin to suppress hepatic glucose production and to stimulate glucose uptake into skeletal muscle (8-10), which in turn leads to insulin...