Abstract 1127: Natural-Killer T Cells are Involved in the Development of Glucose Intolerance and Microalbuminuria in Diet-Induced Obese Mice

Abstract

Introduction: Natural killer T (NKT) cells are a unique subset of T lymphocytes, which recognize glycolipids and integrate inflammation producing pro-inflammatory cytokines on activation. We have demonstrated that NKT cells are present in atherosclerotic lesions and play a pivotal role in atherogenesis. NKT cells also reside in visceral adipose tissues, however, their pathogenic role has not been studied in metabolic derangements. Methods and Results: To determine whether NKT cells are involved in the development of metabolic phenotypes, male β 2 microglobulin knockout (KO) mice, which lack T cells and NKT cells, and C57BL/6J (WT) mice were fed an western diet (WD) containing 21% fat and 0.15% cholesterol or a chow diet for 13 weeks. In both KO (n=14) and WT (n=10) mice fed WD, visceral adipose-tissue weight, adipose cell size, and plasma leptin and non-HDL cholesterol levels were significantly increased compared to those fed a chow ( p< 0.05) but did not differ between KO and WT mice. However, in KO mice fed WD, impaired glucose tolerance (plasma glucose 15 minutes after intraperitoneal glucose injection, 228±7 vs 343±31 mg/dl, p< 0.001) and microalbuminuria (urine albumin/creatinin ratio, 10±1 vs 24±2 μg/mg, p< 0.0001) were significantly ameliorated, but not in WT mice. Plasma TNF-α was significantly lower in KO mice than in WT mice (29±6 vs 85±40 pg/ml, p< 0.05). Immunohistochemical staining of visceral adipose tissues revealed that F4/80 (+) macrophages in KO mice were markedly reduced to 34% of those in WT mice ( p< 0.0001). To further confirm that NKT cells can aggravate metabolic derangements, WT mice received α-galactosylceramide (0.1μg/g), which specifically activates NKT cells, (αgC, n=5) or saline (PBS, n=5) injection after 13 weeks of feeding WD. In αgC mice, impaired glucose tolerance (347±9 vs 308±13 mg/dl, p< 0.05) and microalbuminuria (35±8 vs 17±1 μg/mg, p< 0.05) were significantly exacerbated as compared to PBS mice. Conclusions: NKT cells enhance chronic inflammation in visceral adipose tissues and contribute to the development of metabolic derangements in diet-induced obese mice. NKT cells may be novel therapeutic targets in the prevention of metabolic syndrome.