Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity.
Vascular dysfunction is a major complication of metabolic disorders such as diabetes and obesity. The current studies were undertaken to determine whether inflammatory responses are activated in the vasculature of mice with diet-induced obesity, and if so, whether Toll-Like Receptor-4 (TLR4), a key mediator of innate immunity, contributes to these responses. Mice lacking TLR4 (TLR4(-/-)) and wild-type (WT) controls were fed either a low fat (LF) control diet or a diet high in saturated fat (HF) for 8 weeks. In response to HF feeding, both genotypes displayed similar increases of body weight, body fat content, and serum insulin and free fatty acid (FFA) levels compared with mice on a LF diet. In lysates of thoracic aorta from WT mice maintained on a HF diet, markers of vascular inflammation both upstream (IKKbeta activity) and downstream of the transcriptional regulator, NF-kappaB (ICAM protein and IL-6 mRNA expression), were increased and this effect was associated with cellular insulin resistance and impaired insulin stimulation of eNOS. In contrast, vascular inflammation and impaired insulin responsiveness were not evident in aortic samples taken from TLR4(-/-) mice fed the same HF diet, despite comparable increases of body fat mass. Incubation of either aortic explants from WT mice or cultured human microvascular endothelial cells with the saturated FFA, palmitate (100 micromol/L), similarly activated IKKbeta, inhibited insulin signal transduction and blocked insulin-stimulated NO production. Each of these effects was subsequently shown to be dependent on both TLR4 and NF-kappaB activation. These findings identify the TLR4 signaling pathway as a key mediator of the deleterious effects of palmitate on endothelial NO signaling, and are the first to document a key role for TLR4 in the mechanism whereby diet-induced obesity induces vascular inflammation and insulin resistance.
Kim
Francis
F
Department of Medicine, University of Washington, Seattle, WA 98104, USA. fkim@u.washington.edu
Pham
Matilda
M
Luttrell
Ian
I
Bannerman
Douglas D
DD
Tupper
Joan
J
Thaler
Joshua
J
Hawn
Thomas R
TR
Raines
Elaine W
EW
Schwartz
Michael W
MW
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001823:Body Composition / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D002478:Cells, Cultured; D004041:Dietary Fats; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009924:Organ Culture Techniques; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D007328:Insulin; D053594:Myeloid Differentiation Factor 88; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha; D019308:Palmitic Acid; D053592:Interleukin-1 Receptor-Associated Kinases