Abstract
Current estimates suggest that over one-third of the adult population has metabolic syndrome and three-fourths of the obese population has non-alcoholic fatty liver disease (NAFLD). Inflammation in metabolic tissues has emerged as a universal feature of obesity and its co-morbidities, including NAFLD. Natural Killer T (NKT) cells are a subset of innate immune cells that abundantly reside within the liver and are readily activated by lipid antigens. There is general consensus that NKT cells are pivotal regulators of inflammation; however, disagreement exists as to whether NKT cells exert pathogenic or suppressive functions in obesity. Here we demonstrate that CD1d−/− mice, which lack NKT cells, were more susceptible to weight gain and fatty liver following high fat diet (HFD) feeding. Compared with their WT counterparts, CD1d−/− mice displayed increased adiposity and greater induction of inflammatory genes in the liver suggestive of the precursors of NAFLD. Calorimetry studies revealed a significant increase in food intake and trends toward decreased metabolic rate and activity in CD1d−/− mice compared with WT mice. Based on these findings, our results suggest that NKT cells play a regulatory role that helps to prevent diet-induced obesity and metabolic dysfunction and may play an important role in mechanisms governing cross-talk between metabolism and the immune system to regulate energy balance and liver health.
Highlights
Inflammatory processes in metabolically-active tissues have emerged as a universal feature of obesity and its co-morbidities, including non-alcoholic fatty liver disease (NAFLD)
These data suggest that the protective role of Natural killer T (NKT) cells in obesity could be due to regulation of food intake during high fat diet (HFD)-induced obesity
We further observed a significant increase in monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1 in the liver of CD1d2/2 mice (Figure 7A)
Summary
Inflammatory processes in metabolically-active tissues have emerged as a universal feature of obesity and its co-morbidities, including non-alcoholic fatty liver disease (NAFLD). Natural killer T (NKT) cells constitute a unique subset of immune cells that are present in various peripheral organs, such as the liver where they represent 30–50% of total liver lymphocytes [8,9]. NKT cells express a semi-invariant T cell receptor that recognizes glycolipid antigens presented by the MHC class I-like molecule CD1d. A variety of NKT cell populations have been identified, including Type I, Type II, and NKT-like cells [10,11], Type I represents the vast majority of NKT cells and is the best characterized subset in mouse and human. Type I NKT cells express a TCR composed by rearrangement of the Va14 gene segment (or Va24 in human) to the Ja18 segment. CD1d2/2 mice lack both Type I and Type II NKT cells, as CD1d is required for positive selection of both subsets in the thymus
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