1α,25(OH)2D3 remodels γδ T cell metabolism and ameliorates insulin resistance

Epidemiological studies have showed that vitamin D deficiency was correlated with increased risk of insulin resistance and type 2 diabetes. Although immune cells triggered chronic inflammation as a central link between obesity and insulin resistance, how vitamin D affects metabolic remodeling in immune cells to control inflammation and insulin resistance has not been well characterized. Here we defined a critical role of 1α,25(OH)2D3 in regulating glycolysis metabolism, protecting against inflammation and alleviating insulin resistance. Mechanistically, 1α,25(OH)2D3-VDR promote fructose-1,6-bisphosphatase (FBP1) expression to repress glycolysis in γδ T cells, thereby inhibiting Akt/p38 MAPK phosphorylation and reducing inflammatory cytokines production. Notably, therapeutic administration of 1α,25(OH)2D3 restrains inflammation in adipose-resident γδ T cells and ameliorates systemic insulin resistance in obesity mice. Collectively, these findings show that 1α,25(OH)2D3 has an important role in maintaining γδ T cells homeostasis via orchestrating metabolic programs, and is highly promising target for preventing obesity, inflammation and insulin resistance.