Large adipocytes function as antigen-presenting cells to activate CD4+ T cells via upregulating MHCII in obesity

Abstract

Background/Objectives:Although obesity is associated with low-grade inflammation and metabolic disorders, clinical studies suggested some obese people were metabolically healthy with smaller adipocyte size compared with metabolically abnormal obese (MAO). This indicated adipocyte size may be an important predictor underlay the distinction between MAO and metabolically healthy obese. As recent study has shown that adipocytes expressed class II major histocompatibility complex (MHCII), which functioned as APCs during obesity. However, the relationship between adipocyte hypertrophy and MHCII expression was not involved. Here we hypothesize that hypertrophic adipocytes could be associated with upregulating MHCII to influence adipose tissue metabolism.Methods:Adipocytes were sorted by fluorescence-activated cell sorting (FACS) according to the cell size from MAO mice. The activation of MHCII, T cells and related signaling molecules were examined by FACS, ELISA and western blotting. 3T3-L1 cell line and primary adipocytes were used to examine the effect of free fatty acids (FFA) on adipocytes enlargement and MHCII expression.Results:MAO mice had a significant increase in adipocytes size and FFA concentration. The large adipocytes from both obese and non-obese mice expressed higher levels of MHCII than small adipocytes. Importantly, large adipocytes from obese mice stimulated CD4+ T cells to secrete more interferon (IFN)-γ. Furthermore, the activation of the JNK-STAT1 pathway was involved in upregulation of MHCII in large adipocytes. In vitro FFA treatment promoted adipocyte hypertrophy and expression of MHCII-associated genes.Conclusions:This study demonstrates that large adipocytes highly express MHCII and function as APC to stimulate IFN-γ-expressing CD4+ T cells, in which FFA may have important roles before IFN-γ elevated. These findings suggest that adipocyte hypertrophy, rather than overall obesity, is the major contributor to adipose tissue inflammation and insulin resistance.

IRF3 promotes adipose inflammation and insulin resistance and represses browning

“…These genes include IRF3 itself, of course, but also a large number of class I MHC genes (H2-Q1, H2-Q2, H2-Q6, H2-Q8, H2-K1, H2-K2, H2-Bl, H2-D1, H2Gs10, and H2-T23), all induced by IRF3-2D and repressed by shIRF3. This striking finding is consistent with the proposed role for adipocytes as antigen-presenting cells playing an early role in the inflammatory reaction to overnutrition (6,26). Gene set enrichment analysis identified genes from immunerelated pathways as among the strongest coordinately regulated groups (Supplemental Tables 3 and 4).…”

“…It has been reported that during obesity changes in T cells precede changes in adipose tissue macrophages (50). It was recently proposed that adipocytes can act as antigen-presenting cells via the expression of MHC components, and that this acts as an early trigger in the activation of T cells (6,26). Our results suggest that IRF3 is an early driver of this process, and may thus serve as a critical link between overnutrition and the rest of the well-studied inflammatory cascade in obese adipose tissue.…”

Adrenomedullin 2 Improves Early Obesity-Induced Adipose Insulin Resistance by Inhibiting the Class II MHC in Adipocytes

“…However, the exact type of APC that presents the antigen to the adipose T cells in early obesity remains largely unknown. Previous results show that adipocytes have antigen presentation function and might be the APCs in WAT (19,22). Consistently, we also found the expression of MHCII in adipocytes.…”

“…It was reported that IFNg induced MHCII expression in adipocytes (19,22). Similarly, IFNg treatment dramatically increased the mRNA and protein level of MHCII in cultured adipocytes in a dose-dependent manner (Supplementary Fig.…”

Gene expression profile of subcutaneous adipose tissue in BMI-discordant monozygotic twin pairs unravels molecular and clinical changes associated with sub-types of obesity

“…The coexistence of mitochondrial pathway downregulation, large adipocyte size, inflammatory pathway upregulation in SAT and higher circulating levels of insulin in the heavy twins in Cluster 3 suggests that these phenomena may be biologically connected. Interestingly, large adipocytes have also previously been suspected to be linked to mitochondrial downregulation 21 and inflammation in AT, 55 and mitochondrial dysfunction and lowgrade inflammation co-occur in insulin-resistant subjects' AT. 56 However, the mechanisms underpinning these connections require further studies.…”