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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Immunity and Disease Prevention Research » Research » Publications at this Location » Publication #281123
Title: Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin

Author
item JANG, HYUN-JU - University Of Alabama
item RIDGEWAY, SIMONE - University Of Alabama
item VASHISTA, PRATIBHA - University Of Alabama
item Hwang, Daniel
item QUON, MICHAEL - University Of Maryland
item KIM, JEONG-A - University Of Alabama

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/19/2013
Publication Date: 5/15/2013
Citation: Jang, H., Ridgeway, S.D., Vashista, P., Hwang, D.H., Quon, M.J., Kim, J. 2013. Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin. American Journal of Physiology - Endocrinology and Metabolism. 304(10):E1077-E1088. First e-published 03/26/2013. DOI:10.1152/ajpendo.00578.2012.

Interpretive Summary: Saturated fatty acids in cell culture system or high fat diet in animal model induced endoplasmic reticulum (ER) stress leading to pro-inflammatory responses and insulin resistance in vascular tissue. High fat diet-induced insulin resistance was abolished in TLR2 knockout mice suggesting that such effects are mediated through TLR2.

Technical Abstract: Rationale - Obesity is characterized by a chronic pro-inflammatory state that promotes insulin resistance in liver, adipose tissue, and skeletal muscle as well as impairing insulin action in vascular endothelium that contributes to endothelial dysfunction. Cadiovascular complications of obesity are due, in part, to reciprocal relationships between insulin resistance and endothelial function. Saturated fatty acid (SFA) stimulates toll-like receptors and causes insulin resistance. However, it is not known whether TLR2 mediates impairment of vascular actions of insulin in response to high fat diet (HFD). Objective – We examined the role of TLR2 to mediate impairment of vascular actions of insulin leading to endothelial dysfunction in response to HFD or SFA. Methods and Results – Treatment of cells with SFA stimulated expression of pro-inflammatory cytokines and splicing of X box protein (XBP)-1 that were inhibited by knock-down of TLR2 in primary endothelial cells. Knock-down of XBP-1 or inositol requiring enzyme 1alpha (IRE-1alpha) inhibited SFA-stimulated expression of TNF-alpha. Thus, SFA stimulates unfolding protein response and pro-inflammatory response through activation of TLR2. Knock-down of TLR2 also prevented SFA-mediated impairment of insulin stimulated eNOS phosphorylation and NO production. Moreover, mesenteric arteries isolated from TLR2 knock-out mice on a HFD were protected from impairment of insulin-stimulated vasorelaxation when compared with arteries isolated from wild type mice on a HFD. Conclusion –TLR2 in vascular endothelium plays an important role in HFD-induced pro-inflammatory responses and ER stress that contribute to impairment of vascular actions of insulin.