Natural killer T cells in adipose tissue prevent insulin resistance
Henk S. Schipper, … , Marianne Boes, Eric Kalkhoven
Henk S. Schipper, … , Marianne Boes, Eric Kalkhoven
Published August 6, 2012
Citation Information: J Clin Invest. 2012;122(9):3343-3354. https://doi.org/10.1172/JCI62739.
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Research Article Metabolism

Natural killer T cells in adipose tissue prevent insulin resistance

Abstract

Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell–deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue–resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue–resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance.

Authors

Henk S. Schipper, Maryam Rakhshandehroo, Stan F.J. van de Graaf, Koen Venken, Arjen Koppen, Rinke Stienstra, Serge Prop, Jenny Meerding, Nicole Hamers, Gurdyal Besra, Louis Boon, Edward E.S. Nieuwenhuis, Dirk Elewaut, Berent Prakken, Sander Kersten, Marianne Boes, Eric Kalkhoven

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Figure 4

Absence of CD1d-restricted iNKT cells is associated with adipocyte dysfunction in lean mice.

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Absence of CD1d-restricted iNKT cells is associated with adipocyte dysfu...
(A) Microarray-based fold change versus fold change scatter plot comparing gene expression profiles in WT HFD group (x axis) and Cd1d–/– LFD group (y axis). Genes of interest encoding classical inflammatory markers or adipokines are highlighted in red (upregulated) or blue (downregulated). Fold changes represent the mean of 4–6 mice per experimental group. (B) Quantitative RT-PCR of selected classical inflammatory markers in AT. Mean expression in WT LFD mice was set at 1. Fold changes were normalized for housekeeping gene expression (36B4). n = 9 mice per group; total 27 mice. (C) H&E staining of VAT from WT and CD1d-null mice after 19 weeks of LFD feeding. Scale bars: 100 εm. VAT adipocyte sizes (area per adipocyte, μm2) in LFD-fed WT and CD1d-null mice are presented. Box plots show the median area per adipocyte for both groups, and 10th to 90th percentiles. n = 10 mice per group; total 20 mice. (D and E) Leptin and adiponectin mRNA expression in VAT were determined by quantitative RT-PCR (n = 9 mice per group; total 27 mice). Leptin and adiponectin protein levels were analyzed in plasma from LFD-fed CD1d-null mice and WT mice on a LFD and HFD. n = 10 mice per group; total 30 mice.