Editors' ChoiceMetabolic Disease

iNKT Cells Live Off the Fat of the Land

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Science Translational Medicine  25 Apr 2012:
Vol. 4, Issue 131, pp. 131ec74
DOI: 10.1126/scitranslmed.3004182

Obsesity is one of the leading preventable causes of death worldwide. Following current trends, by the year 2030 nearly every American will be overweight or obese. The rates of obesity-related metabolic conditions, such as insulin resistance and hepatic steatosis, are equally alarming. In response to this epidemic, scientists have been searching for new therapeutic avenues to treat and prevent obesity and its associated metabolic diseases.

Obesity triggers a low-grade systemic inflammation, which in turn interferes with metabolic pathways, leading to obesity-associated metabolic diseases. The underlying mechanisms that initiate and sustain chronic inflammation in obesity remain to be defined. Invariant natural killer T (iNKT) cells, a subset of T lymphocytes, have been shown to react with lipids and regulate inflammatory responses. Once stimulated, iNKT cells can produce large amounts of cytokines with both pro- and anti-inflammatory properties. Now, Wu et al. test the hypothesis that lipid excess in obesity activates iNKT cells, which in turn promotes obesity-induced inflammation, insulin resistance, and hepatic steatosis.

First, the authors examined whether iNKT cells can respond to lipid excess by comparing liver and white adipose tissue (WAT) in mice fed high-fat diets, low-fat diets, or regular chow. The authors found that iNKT cells were activated by dietary lipid excess before or around the time of increases in several types of inflammatory cytokines in liver and WAT of obese mice. In both a diet-induced and genetic mouse model of obesity, iNKT cell deficiency ameliorated tissue inflammation and protected against obesity-induced insulin resistance and hepatic steatosis. Furthermore, chronic iNKT cell stimulation exacerbated tissue inflammation and obesity-associated metabolic diseases.

More research is needed to identify the specific stimuli acting on iNKT cells in obesity. However, the newly found role of iNKT cells linking lipid excess to obesity-induced inflammation suggests that altering iNKT cell function may provide a potential therapeutic solution for treating and preventing obesity-associated metabolic diseases.

L. Wu et al., Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc. Natl. Acad. Sci. U.S.A. 9 April 2012 (10.1073/pnas.1200498109). [Abstract]

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