Increased levels of invariant natural killer T lymphocytes worsen metabolic abnormalities and atherosclerosis in obese mice.
Obesity is a chronic inflammatory state characterized by infiltration of adipose tissue by immune cell populations, including T lymphocytes. Natural killer T (NKT) cells, a specialized lymphocyte subset recognizing lipid antigens, can be pro- or anti-inflammatory. Their role in adipose inflammation continues to be inconclusive and contradictory. In obesity, the infiltration of tissues by invariant NKT (iNKT) cells is decreased. We therefore hypothesized that an excess iNKT cell complement might improve metabolic abnormalities in obesity. Vα14 transgenic (Vα14tg) mice, with increased iNKT cell numbers, on a LDL receptor-deficient (Ldlr(-/-)) background and control Ldlr(-/-) mice were placed on an obesogenic diet for 16 weeks. Vα14tg.Ldlr(-/-) mice gained 25% more weight and had increased adiposity than littermate controls. Transgenic mice also developed greater dyslipidemia, hyperinsulinemia, insulin resistance, and hepatic triglyceride accumulation. Increased macrophage Mac2 immunostaining and proinflammatory macrophage gene expression suggested worsened adipose inflammation. Concurrently, these mice had increased atherosclerotic lesion area and aortic inflammation. Thus, increasing the complement of iNKT cells surprisingly exacerbated the metabolic, inflammatory, and atherosclerotic features of obesity. These findings suggest that the reduction of iNKT cells normally observed in obesity may represent a physiological attempt to compensate for this inflammatory condition.
Division of Metabolism, Endocrinology and Nutrition and University of Washington, Seattle, WA.
Savitha
S
Subramanian
Michael S
MS
Turner
Yilei
Y
Ding
Leela
L
Goodspeed
Shari
S
Wang
Jane H
JH
Buckner
Kevin
K
O'Brien
Godfrey S
GS
Getz
Catherine A
CA
Reardon
Alan
A
Chait
D052436:Adipose Tissue, White / Q000276:immunology; D050154:Adiposity; D000818:Animals; D001011:Aorta / Q000276:immunology / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D006937:Hypercholesterolemia / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D055611:Natural Killer T-Cells / Q000276:immunology*; D009765:Obesity / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D013395:Sucrose / Q000009:adverse effects
D013395:Sucrose
adipose tissue; antigens; inflammation; lipids; steatosis