High-fat diet-induced immune dysregulation in Th17/regulatory T cells promotes inflammation through protein kinase A (PKA) and PPAR-γ pathways

Abstract

Abstract Obesity is a hallmark around the globe, which is defined as a complex situation associated with various metabolic abnormalities and cardiovascular diseases. The increasing evidence suggests that type 1 inflammation-associated immune cells are dominant in adipose tissue and exert metabolically deleterious impacts. The precise mechanism of alteration of adipose tissue immune system and its effect on metabolic homeostasis is far from clear. We investigated how a high-fat diet (HFD) alters adipose tissue (AT) immune system and influences the inflammation. HFD consumption amends the metabolic parameters including body weight, glucose, and insulin levels. We noticed that there is increased infiltration of Th17 cells, dendritic cells, and macrophages in AT of mice fed HFD as compared to a normal diet (ND). In mice consuming HFD, we also find a reduction in regulatory T cells as compared to ND. We noticed a higher level of proinflammatory cytokines and chemokines in the HFD group as compared to ND. We also noticed an increase in IL-6 and KLF4 expression in the AT of HFD as compared to ND. Further, an increased level of AT protein kinase A in HFD fed and a decrease in PPAR-γ as compared to ND, suggesting acting as a negative regulator of Th17 cell differentiation. Taken together, these results suggest that HFD induces Th17, macrophage, dendritic cells, inflammatory cytokine and reduces Tregs and PPAR-γ to sustain AT inflammation. This study supports a key role of Th17/Tregs dysregulation and macrophages to induce AT inflammation through PKA and PPAR-γ pathways during obesity. (Supported by NIH grant R01 AI140405). Supported by NIH grant R01 AI140405.