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Toll-like Receptor 2 (TLR2) Deficiency Abrogates Diabetic and Obese Phenotypes while Restoring Endothelial Function via Inhibition of NOX1

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posted on 14.07.2021, 22:12 by Zhen Guo, Yixuan Zhang, Chang Liu, Ji Youn Youn, Hua Linda Cai
We have previously demonstrated a novel role of bone morphogenic protein-4 (BMP4) in inducing NOX1-dependent eNOS uncoupling, endothelial dysfunction, and inflammatory activation in type 2 diabetes mellitus (T2DM). However, it has remained unclear as to how BMP4 activates NOX1 and whether targeting the new mechanistic pathway revealed is effective in preserving endothelial function in T2DM. Here we observed that BMP4 induced marked, time-dependent increase in physiological binding between TLR2 and NOX1 in aortic endothelial cells, as well as increased binding of TLR2 to NOXO1. In high-fat diet fed Tlr2-/- (TLR2 knockout) mice, the body weight gain was significantly less compared to WT (wild-type) mice both in males and females. The high-fat diet induced increases in fasting blood glucose levels, as well as in circulating insulin and leptin levels, were absent in Tlr2-/- mice. High-fat feeding induced increases in overall fat mass, and fat mass of different pockets were abrogated in Tlr2-/- mice. Whereas energy intake was similar in high-fat fed WT and Tlr2-/- mice, TLR2 deficiency resulted in higher energy expenditure attributed to improved physical activity, which was accompanied by restored skeletal muscle mitochondrial function. In addition, TLR2 deficiency recoupled eNOS, reduced total superoxide production, improved H4B and NO bioavailabilities in aortas and restored endothelium-dependent vasorelaxation. Collectively, our data strongly indicate that TLR2 plays important roles in the development of metabolic features of T2DM, and its related endothelial/vascular dysfunction. Therefore, targeting TLR2 may represent a novel therapeutic strategy for T2DM, obesity and cardiovascular complications via specific inhibition of NOX1.

Funding

This study was supported by National Institute of Health National Heart, Lung and Blood Institute (NHLBI) Grants HL077440 (HC), HL088975 (HC), HL142951 (HC) and HL154754 (HC).

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