title: Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin.
abstract: Obesity is characterized by a chronic proinflammatory state that leads to endothelial dysfunction. Saturated fatty acids (SFA) stimulate Toll-like receptors (TLR) that promote metabolic insulin resistance. However, it is not known whether TLR2 mediates impairment of vascular actions of insulin in response to high-fat diet (HFD) to cause endothelial dysfunction. siRNA knockdown of TLR2 in primary endothelial cells opposed palmitate-stimulated expression of proinflammatory cytokines and splicing of X box protein 1 (XBP-1). Inhibition of unfolding protein response (UPR) reduced SFA-stimulated expression of TNFα. Thus, SFA stimulates UPR and proinflammatory response through activation of TLR2 in endothelial cells. Knockdown of TLR2 also opposed impairment of insulin-stimulated phosphorylation of eNOS and subsequent production of NO. Importantly, insulin-stimulated vasorelaxation of mesenteric arteries from TLR2 knockout mice was preserved even on HFD (in contrast with results from arteries examined in wild-type mice on HFD). We conclude that TLR2 in vascular endothelium mediates HFD-stimulated proinflammatory responses and UPR that accompany impairment of vasodilator actions of insulin, leading to endothelial dysfunction. These results are relevant to understanding the pathophysiology of the cardiovascular complications of diabetes and obesity.
authors.affiliation: Dept. of Medicine, Div. of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Jang
authors.forename: Hae-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hwang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quon
authors.forename: Jeong-a
authors.initials: JA
authors.lastname: Kim
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010168:Palmitates / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D056811:Unfolded Protein Response; D014664:Vasodilation / Q000187:drug effects / Q000276:immunology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010168:Palmitates; D051195:Toll-Like Receptor 2
keywords: Toll-like receptor 2; endothelial function; endothelial nitric oxide synthase; inflammation; unfolding protein response; vascular insulin resistance