Abstract
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.
Highlights
Figure 1. 3T3-L1 adipocytes express CD1d and co-stimulatory molecules. (a,b) 3T3-L1 cells before (Pre) or after differentiation (Diff; 3T3-L1-adipocytes) were stained with Oil-red-O. mRNA expression of the mature adipocyte markers Pparg and Fabp[4] (a), Cd1d1, Cd80 and Cd86 (b), were analyzed by qPCR. (c) The Cd1d1 expression of the adipocyte fraction in visceral adipose tissue from WT or CD1d−/− mice was analyzed by qPCR
In the first part of the present study, we have demonstrated that 3T3-L1 adipocytes can present both exogenous and endogenous lipid antigens on CD1d to activate NKT cells, which is consistent with previous reports[23,24]
CD80 but not CD86 is significantly induced when mice are fed high-fat diet (HFD). Both iNKT cells from WT or vNKT cells from Jα18−/− mice responded to 3T3-L1 adipocytes in the absence of an exogenous NKT cell ligand, they stained negative with L363 mAb that is thought to recognize α-GlyCer/CD1d complexes[25]
Summary
Figure 1. 3T3-L1 adipocytes express CD1d and co-stimulatory molecules. (a,b) 3T3-L1 cells before (Pre) or after differentiation (Diff; 3T3-L1-adipocytes) were stained with Oil-red-O. mRNA expression of the mature adipocyte markers Pparg and Fabp[4] (a), Cd1d1, Cd80 and Cd86 (b), were analyzed by qPCR. (c) The Cd1d1 expression of the adipocyte fraction in visceral adipose tissue from WT or CD1d−/− mice was analyzed by qPCR. 3T3-L1 adipocytes express CD1d and co-stimulatory molecules. (a,b) 3T3-L1 cells before (Pre) or after differentiation (Diff; 3T3-L1-adipocytes) were stained with Oil-red-O. MRNA expression of the mature adipocyte markers Pparg and Fabp[4] (a), Cd1d1, Cd80 and Cd86 (b), were analyzed by qPCR. (c) The Cd1d1 expression of the adipocyte fraction in visceral adipose tissue from WT or CD1d−/− mice was analyzed by qPCR. Representative data from at least 3 independent experiments are shown. Data are shown as mean ± s.d. Statistical analysis was performed according to the Student’s t-test. Lack CD1d expression in adipocytes, gain less body weight and exhibit improved insulin sensitivity than littermate control mice when fed a high-fat diet. Mechanisms underlying the development of obesity and insulin resistance are discussed in relation to NKT cell-adipocyte interactions
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