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.

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

“…This protection from high-fat dietinduced adipose tissue insulin resistance was associated with a failure of the high-fat diet to induce expression of inflammatory mediators in WAT. This finding was recently supported by a report that NEFA stimulate proinflammatory pathways and reduce insulin sensitivity in WAT through TLR4 activation [34]. The attenuated effect of LPS on insulininduced glucose uptake in mutant adipocytes may reflect a direct contribution of TLR4 present in adipocytes.…”

Lipid signalling in disease

“…Furthermore, mice that lack TLR4 are substantially protected from the ability of systemic lipid infusion to suppress insulin signalling in muscle and from insulinmediated changes in systemic glucose metabolism 76 .…”

The maternal and fetal impacts of obesity and gestational diabetes on pregnancy outcome

“…Upstream along this pathway, abnormal circulating concentrations of saturated fatty acids also bind and activate immune pattern recognition receptors (toll-like receptors), for which bacterial lipopolysaccharide (LPS) is the usual ligand (see Herrera chapter). 77,79,80 Vitamin D and folate Serum concentrations of vitamin D are lower in obese and overweight individuals, when compared with their lean counterparts. The prevalence of vitamin D deficiency (52-72 nmol/L) is estimated at twice that of the geographically matched population.…”