In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 19 ( 2012-05-08)
Abstract:
Our findings suggest iNKT cells as potential therapeutic targets for obesity-associated metabolic disorders. This could potentially be accomplished by depleting these cells with specific antibodies or by stimulating them with glycolipid antigens that induce production of antiinflammatory cytokines. Collectively, our findings have identified iNKT cells as previously undescribed players in the complex network linking lipid accumulation to inflammation in obesity ( Fig. P1 ). Although our findings indicate that iNKT cells become activated by lipid excess, the mechanisms involved remain unclear. We favor the possibility that dyslipidemia, or high lipid levels in the blood, in obesity modulates the loading of CD1d with accumulated self-lipids. This scenario is supported by published studies that have investigated the response of iNKT cells to a variety of inflammatory stimuli ( 3 ). To complement our studies of iNKT cell-deficient mouse models with a gain-of-function approach, we examined the effects of repeated injection with the prototypical iNKT cell antigen α-GalCer, which is often used to explore the potential therapeutic properties of activated iNKT cells, on inflammatory and metabolic parameters in mice fed a high-fat diet. Although this treatment had no detectable effects on the development of obesity, it impaired insulin sensitivity and exacerbated lipid accumulation in the liver. These alterations in metabolic parameters were associated with increased infiltration of macrophages and CD8 + T cells, or killer T cells, in the liver and white adipose tissue. To investigate the mechanisms by which iNKT cells influence these metabolic parameters, we examined whether the absence of iNKT cells influences inflammatory parameters in metabolically active organs in obese mice. We found that obese iNKT cell-deficient mice accumulated fewer macrophages in both liver and white adipose tissue. iNKT cell or CD1d deficiency was also associated with reduced elevations in the proinflammatory cytokines TNF-α and monocyte chemoattractant protein-1 in the liver and white adipose tissue of obese mice. Conversely, we observed higher levels of the antiinflammatory, insulin-sensitizing, and fat-derived hormone adiponectin in the white adipose tissue of obese iNKT cell-deficient mice compared with obese WT mice. To confirm these findings and to evaluate the potential contribution of other CD1d-restricted T cells, we performed similar experiments with CD1d -deficient mice. CD1d molecules are expressed on the surface of many immune cells and some other cell types, and they function to activate NKT cells. Consistent with our findings for J α 18 -deficient mice, CD1d -deficient mice were partially protected against insulin resistance and fatty liver disease induced by a high-fat diet or leptin receptor deficiency. We next investigated the effects of iNKT cell deficiency on metabolic parameters, using mice deficient in the J α 18 gene, a deficiency that selectively causes them to lack iNKT cells. Mice lacking iNKT cells, compared with WT mice, exhibit reduced immunity against some bacterial and viral infections, increased incidence of some autoimmune diseases, and suppressed allergic airway disease (similar to human asthma). We found that this J α 18 deficiency had a minimal effect on weight gain and did not affect the levels of blood triglycerides or cholesterol; moreover, it did not influence food intake or energy expenditure. Nevertheless, the absence of iNKT cells protected these mice against insulin resistance (a characteristic feature of type 2 diabetes) and excessive lipid accumulation in the liver (a characteristic feature of fatty liver disease, or lipid retention) induced by high-fat diets. We obtained similar results for leptin receptor-deficient db/db mice that lacked iNKT cells because of J α 18 deficiency. We used a model of obesity induced by a high-fat diet and a genetic model of obesity attributable to deficiency in the leptin receptor. We showed that iNKT cells rapidly become activated in settings of dietary lipid excess, as evidenced by induction of the ICOS surface molecule and down-regulation of the NK1.1 (an activating receptor expressed by NK cells and a subset of T cells) surface molecule on these cells, which are hallmarks of iNKT cell activation. iNKT cells also progressively acquired the capacity to produce proinflammatory messenger molecules called cytokines, such as TNF-α and IFN-γ. These alterations in iNKT cells contributed to a profile generally skewed toward proinflammatory cytokine production compared with iNKT cells from mice fed a low-fat diet. This was true in multiple organs, including liver and white adipose tissue, that play a critical role in obesity-triggered inflammation. Studies over the past decade have revealed that obesity is associated with a low-level, chronic inflammation that plays an important role in the development of insulin resistance and type 2 diabetes by interfering with insulin-signaling pathways ( 1 ). We investigated the role of immune cells called invariant natural killer T (iNKT) cells in this process. iNKT cells are a subset of immune cells that bridge the natural and acquired immune systems, exhibiting properties that are similar to both natural killer (NK) cells of the natural immune system and T cells of the acquired immune system ( 2 ). iNKT cells react with lipid antigens, such as the sea sponge-derived glycolipid α-galactosylceramide (α-GalCer) bound by the self-protein CD1d at the surface of other cell types. iNKT cells predominantly play a regulatory role in the immune system. We found that these cells play a pathogenic role in obesity-associated inflammation, suggesting iNKT cells as potential therapeutic targets for obesity-associated diseases.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1200498109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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