title: TNF-α impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity.
abstract: We tested the hypothesis that high fat (HF) feeding results in endothelial dysfunction in resistance arteries of epididymal white adipose tissue (eWAT) and is mediated by adipose tissue inflammation. When compared with normal chow (NC)-fed mice (n = 17), HF-fed male B6D2F1 mice were glucose intolerant and insulin resistant as assessed by glucose tolerance test (area under the curve; HF, 18,174 ± 1,889 vs. NC, 15,814 ± 666 mg·dl(-1)·min(-1); P < 0.05) and the homeostatic model assessment (HF, 64.1 ± 4.3 vs. NC, 85.7 ± 6.4; P = 0.05). HF diet-induced metabolic dysfunction was concomitant with a proinflammatory eWAT phenotype characterized by greater macrophage infiltration (HF, 3.9 ± 0.8 vs. NC, 0.8 ± 0.4%; P = 0.01) and TNF-α (HF, 22.6 ± 4.3 vs. NC, 11.4 ± 2.5 pg/dl; P < 0.05) and was associated with resistance artery dysfunction, evidenced by impaired endothelium-dependent dilation (EDD) (maximal dilation; HF, 49.2 ± 10.7 vs. NC, 92.4 ± 1.4%; P < 0.01). Inhibition of nitric oxide (NO) synthase by N(ω)-nitro-L-arginine methyl ester (L-NAME) reduced dilation in NC (28.9 ± 6.3%; P < 0.01)- and tended to reduce dilation in HF (29.8 ± 9.9%; P = 0.07)-fed mice, eliminating the differences in eWAT artery EDD between NC- and HF-fed mice, indicative of reduced NO bioavailability in eWAT resistance arteries after HF feeding. In vitro treatment of excised eWAT arteries with recombinant TNF-α (rTNF) impaired EDD (P < 0.01) in NC (59.7 ± 10.9%)- but not HF (59.0 ± 9.3%)-fed mice. L-NAME reduced EDD in rTNF-treated arteries from both NC (21.9 ± 6.4%)- and HF (29.1 ± 9.2%)-fed mice (both P < 0.01). In vitro treatment of arteries with a neutralizing antibody against TNF-α (abTNF) improved EDD in HF (88.2 ± 4.6%; P = 0.05)-fed mice but was without effect on maximal dilation in NC (89.0 ± 5.1%)-fed mice. L-NAME reduced EDD in abTNF-treated arteries from both NC (25.4 ± 7.5%)- and HF (27.1 ± 16.8%)-fed mice (both P < 0.01). These results demonstrate that inflammation in the visceral adipose tissue resulting from diet-induced obesity impairs endothelial function and NO bioavailability in the associated resistance arteries. This dysfunction may have important implications for adipose tissue blood flow and appropriate tissue function.
authors: Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, 84148, USA.
authors: Anthony J
authors: AJ
authors: Donato
authors: Grant D
authors: GD
authors: Henson
authors: R Garrett
authors: RG
authors: Morgan
authors: Ryley A
authors: RA
authors: Enz
authors: Ashley E
authors: AE
authors: Walker
authors: Lisa A
authors: LA
authors: Lesniewski
mesh_terms: D052436:Adipose Tissue, White / Q000098:blood supply*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001158:Arteries / Q000276:immunology / Q000503:physiopathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018149:Glucose Intolerance / Q000276:immunology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism*; D007333:Insulin Resistance; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000276:immunology* / Q000503:physiopathology; D015434:Panniculitis / Q000276:immunology / Q000503:physiopathology; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D014655:Vascular Resistance; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase