krn-7000 and Insulin-Resistance

It has been shown that CD1d expression and glycolipid-reactive, CD1d-restricted NKT cells exacerbate the development of obesity and insulin resistance in mice. However, the relevant CD1d-expressing cells that influence the effects of NKT cells on the progression of obesity remain incompletely defined. In this study, we have demonstrated that 3T3-L1 adipocytes can present endogenous ligands to NKT cells, leading to IFN-γ production, which in turn, stimulated 3T3-L1 adipocytes to enhance expression of CD1d and CCL2, and decrease expression of adiponectin. Furthermore, adipocyte-specific CD1d deletion decreased the size of the visceral adipose tissue mass and enhanced insulin sensitivity in mice fed a high-fat diet (HFD). Accordingly, NKT cells were less activated, IFN-γ production was significantly reduced, and levels of adiponectin were increased in these animals as compared with control mice on HFD. Importantly, macrophage recruitment into the adipose tissue of adipocyte-specific CD1d-deficient mice was significantly blunted. These findings indicate that interactions between NKT cells and CD1d-expressing adipocytes producing endogenous NKT cell ligands play a critical role in the induction of inflammation and functional modulation of adipose tissue that leads to obesity.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Antigen Presentation; Antigens, CD1d; B7-1 Antigen; Diet, High-Fat; Disease Models, Animal; Disease Progression; Galactosylceramides; Insulin Resistance; Interferon-gamma; Lymphocyte Activation; Macrophage Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Natural Killer T-Cells; Obesity

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 obesity-associated 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.

Topics: Adipose Tissue, White; Animals; Antigens, CD1d; CD8-Positive T-Lymphocytes; Cells, Cultured; Cytokines; Dietary Fats; Fatty Liver; Female; Flow Cytometry; Galactosylceramides; Inflammation; Inflammation Mediators; Insulin Resistance; Lipids; Lymphocyte Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells; Obesity