High-Fat Diet-Induced Dysregulation of Immune Cells Correlates with Macrophage Phenotypes and Chronic Inflammation in Adipose Tissue

Obesity is a complex disease associated with various metabolic abnormalities, cardiovascular diseases, and low-grade chronic inflammation. Inflammation associated with T helper 1 (Th1) immune cells is dominant in adipose tissue (AT) and exerts metabolically deleterious impacts. The precise mechanism of alteration in AT immune system and its effect on metabolic homeostasis remains unclear. In this study, we investigated how a high-fat diet (HFD) alters the AT immune response and influences inflammation during obesity. HFD consumption amends the metabolic parameters, including body weight, glucose, and insulin levels. We observed increased infiltration of Th17 cells, a subset of dendritic cells (CD103+), and M1 macrophages in AT of mice fed HFD compared to those fed a normal diet (ND). In mice that were fed HFD, we also observed a reduction in regulatory T cells (Tregs) relative to the numbers of these cells in mice fed ND. Corresponding with this, mice in the HFD group exhibited higher levels of proinflammatory cytokines and chemokines than those in the ND group. We also observed alterations in signaling pathways, including increased protein expression of IRF3, TGFβ1, and mRNA expression of IL-6, KLF4, and STAT3 in the AT of the mice fed HFD as compared to those fed ND. Further, HFD-fed mice exhibited decreased protein expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) compared to mice fed ND, suggesting that PPAR-γ functions as a negative regulator of Th17 cell differentiation. These results suggest that HFD induces increased levels of inflammatory cytokines and key immune cells, including Th17, M1 macrophages, and CD103+ dendritic cells, and reduces levels of PPAR-γ and Tregs to sustain AT inflammation. This study supports the notion that dysregulation of Th17/Tregs, which polarizes macrophages towards M1 phenotypes in part through TGFβ1-IRF3-STAT3 and negatively regulates PPAR-γ mediated pathways, results in AT inflammation during obesity.