Natural Killer T Cells Are Involved in Adipose Tissues Inflammation and Glucose Intolerance in Diet-Induced Obese Mice

Abstract

Background-Macrophage and lymphocyte infiltration in adipose tissue may contribute to the pathogenesis of obesity-mediated metabolic disorders. Natural killer T (NKT) cells, which integrate proinflammatory cytokines, have been demonstrated in the atherosclerotic lesions and in visceral adipose tissue. Objective-To determine whether NKT cells are involved in glucose intolerance and adipose tissue inflammation in diet-induced obese mice. Methods and Results-To determine whether NKT cells are involved in the development of glucose intolerance, male ␤ 2 -microglobulin knockout (KO) mice lacking NKT cells and C57BL/6J (wild-type) mice were fed with a high-fat diet (HFD) for 13 weeks. Body weight and visceral obesity were comparable between wild-type and KO mice. However, macrophage infiltration was reduced in adipose tissue and glucose intolerance was significantly ameliorated in KO mice.To further confirm that NKT cells are involved in these abnormalities, ␣-galactosylceramide, 0.1 g/g body weight, which specifically activates NKT cells, was administered after 13 weeks of HFD feeding. ␣-Galactosylceramide significantly exacerbated glucose intolerance and macrophage infiltration as well as cytokine gene expression in adipose tissue. O besity, specifically visceral obesity, increases the risk for metabolic disorders, such as type 2 diabetes mellitus, dyslipidemia, and hypertension as well as atherosclerotic cardiovascular diseases. Previous studies have demonstrated that the accumulation of macrophages within adipose tissue is well documented in obese individuals and that adipose tissue inflammation plays an important role in the pathogenesis of these metabolic disorders. 1,2 Macrophages are attracted by chemokines, such as monocyte chemoattractant protein 1 (MCP-1), and contribute to local inflammation through the release of other inflammatory cytokines, such as tumor necrosis factor (TNF) ␣. In high-fat diet (HFD)-fed obese mice, it has been shown that infiltration of macrophages into adipose tissue coincides with the occurrence of obesitymediated metabolic disorders. 2 The important role of adipose tissue macrophages in the pathogenesis of metabolic disorders has further been supported by recent data in C-C motif chemokine receptor 2 (CCR2)-deficient mice. 3 The CCR2 Ϫ/Ϫ mice exhibited a reduction in adipose tissue macrophages in association with an improvement of glucose homeostasis and insulin sensitivity. However, the abolished monocyte and macrophage recruitment into peripheral tissue via interaction with MCP-1 could not completely inhibit HFD-mediated metabolic disorders, suggesting that other inflammatory cells may play a role in this context. Wu et al 4 and Rocha et al 5 demonstrated that CD3-positive T lymphocytes are present in human adipose tissue; and regulated upon activation, normal T cell expressed secreted (RANTES), a T-cell-specific chemokine, and its respective receptor CCR5 are expressed in adipose tissue from obese patients. However, the role of other types of lymphocytes in adipose tissue inflam...

Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

“…NKT cells react to lipid antigens presented on CD1d, which results in the secretion of various cytokines (IL-4, IL-10, IFN-g, and TNF-a) that may elicit Th1, Th2, and Treg responses. Experiments with mice with loss-and gain-offunction in NKT activity revealed a gamut of outcomes ranging from beneficial (21)(22)(23)(24)(25), to null (26), to detrimental (27)(28)(29) effects of NKT cells on metabolism. These divergent effects may result from the various strategies applied (CD1d 2/2 that affects all NKT cells vs. Ja18 2/2 that affects only type 1 NKT cells), various diets, various durations, or other local, yet not identified factors.…”

Lymphocytes in obesity-related adipose tissue inflammation

“…Specific NKT cell receptors interact with CD1d-related lipid and glycolipid antigens, thus providing a potential link between obesity, autoimmunity and inflammatory diseases [63,64]. NKT cells could contribute to the development of visceral WAT inflammation during obesity, since HFD-fed NKT-deficient mice (β 2 -microglobulin knockout mice) show lower macrophage accumulation and better glucose tolerance than control mice, with no differences in body weights [65]. However, it has recently been demonstrated that the aforementioned effects of NKT cell deletion on metabolism can only occur in the absence of CD8 + T cells [66].…”

Activation of Natural Killer T Cells Ameliorates Postinfarct Cardiac Remodeling and Failure in Mice

“…Indeed, we have shown that iNKT cells activate vascular wall inflammation in atherogenesis and adipose tissue inflammation in obesity-induced glucose intolerance. 7,8 On the other hand, iNKT cells play a protective role against autoimmune and inflammatory diseases such as type 1 diabetes, 9,10 allergic encephalomyelitis, 9,11 and rheumatoid arthritis. 12 These findings suggest that iNKT cells may have bidirectional effects on tissue inflammation.…”