Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice

Abstract

Obesity triggers a low-grade systemic inflammation, which plays an important role in the development of obesity-associated metabolic diseases. In searching for links between lipid accumulation and chronic inflammation, we examined invariant natural killer T (iNKT) cells, a subset of T lymphocytes that react with lipids and regulate inflammatory responses. We show that iNKT cells respond to dietary lipid excess and become activated before or at the time of tissue recruitment of inflammatory leukocytes, and that these cells progressively increase proinflammatory cytokine production in obese mice. Such iNKT cells skew other leukocytes toward proinflammatory cytokine production and induce an imbalanced proinflammatory cytokine environment in multiple tissues. Further, iNKT cell deficiency ameliorates tissue inflammation and provides protection against obesity-induced insulin resistance and hepatic steatosis. Conversely, chronic iNKT cell stimulation using a canonical iNKT cell agonist exacerbates tissue inflammation and obesityassociated metabolic disease. These findings place iNKT cells into the complex network linking lipid excess to inflammation in obesity and suggest new therapeutic avenues for obesity-associated metabolic disorders.cluster of differentiation 1d | glycolipid-reactive T cells | alpha-galactosylceramide | obesity-induced inflammation

Natural killer T cells in adipose tissue prevent insulin resistance

“…As IFN-γ has been associated with insulin resistance in cultured adipocytes (56,57) and in vivo (14,58), these findings suggest that, in contrast to the protective role we observed under LFD conditions, iNKT cells could contribute to the development of insulin resistance under other conditions. Indeed, some recent reports indicate that depletion of iNKT cells can improve insulin sensitivity under HFD conditions (59)(60)(61). The exact role of iNKT cells under HFD conditions is, however, unclear, as other studies, and the present study, failed to detect a prominent effect of iNKT cell depletion on glucose homeostasis (26)(27)(28).…”

Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

“…Although the pathological impact of both innate and adaptive immune cells, including myeloid cells, B cells, T cells, and natural killer T (NKT) cells, has been documented in DIO models (1,7,9,11,12,28,29), the molecular signaling pathways that mediate their effects remain largely unexplored and unclear. In the present study, we have identified the transcription factor Stat3 as an important mediator of T-cell-driven inflammation in adipose tissue of DIO mice.…”

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.…”