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Toll‐like receptor 4 deficiency attenuates insulin resistance and endothelial dysfunction associated with obesity and diabetes in mice
Author(s) -
Liang CF,
Xu Aimin,
Vanhoutte Paul M
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.571.5
Subject(s) - medicine , endocrinology , insulin resistance , endothelial dysfunction , oxidative stress , insulin , tlr4 , diabetes mellitus , endothelium , apocynin , chemistry , inflammation , nadph oxidase
The present study analyzes, in mice with loss‐of‐function mutation of TLR4, the role of TLR4, a target for saturated fatty acids, in modulating metabolism and endothelial function. A type‐2 diabetes model with double knockout (DKO) of leptin receptors (Lepr) and TLR4, was obtained by crossing Lepr db/+ and TLR4 −/−− mice. Glucose and insulin tolerance tests were performed. Isometric tension was measured in carotid artery rings with or without endothelium. DKO mice had lower fasting serum levels of glucose, triglycerides and cholesterol and better insulin sensitivity than Lepr db/db control mice. Acetylcholine‐induced endothelium‐dependent contractions (EDCF‐responses) of the carotid arteries were enhanced by genetic obesity, but were attenuated in DKO mice. They were inhibited by indomethacin and SC560, suggesting the involvement of COX‐1. Apocynin, MnTMPyP, catalase, DPI, DETCA, but not deferoxamine and tiron inhibited EDCF‐responses, suggesting a role for H2O2. Inhibitors including SP600128 [JNK], PD98058 [ERK] and SB203508 [MAPK] reduced the contractions in arteries of control but not of DKO mice indicating a mechanism downstream of TLR4. Rotenone and antimycin A inhibited the EDCF‐response implying that mitochondria are involved. Thus, TLR4 deficiency can prevent insulin resistance and endothelial dysfunction possibly by decreasing oxidative stress in mitochondria.