1α,25(OH)(2)D(3) ameliorates insulin resistance by alleviating γδ T cell inflammation via enhancing fructose-1,6-bisphosphatase 1 expression

Background: Chronic inflammation caused by immune cells is the central link between obesity and insulin resistance. Targeting the inflammatory process is a highly promising method for reversing systemic insulin resistance. Methods: Blood samples were prospectively collected from 68 patients with type 2 diabetes. C57BL/6J mice were fed either a high-fat diet (HFD) or normal chow (NC). We performed phenotypical and functional analyses of immune cells using flow cytometry. Vitamin D receptor (VDR) knockout γδ T cells were constructed using Cas9-gRNA targeted approaches to identify 1α,25(OH)(2)D(3)/VDR signaling pathway-mediated transcriptional regulation of fructose-1,6-bisphosphatase (FBP1) in γδ T cells. Results: Serum vitamin D deficiency aggravates inflammation in circulating γδ T cells in type 2 diabetes patients. We defined a critical role for 1α,25(OH)(2)D(3) in regulating glycolysis metabolism, protecting against inflammation, and alleviating insulin resistance. Mechanistically, 1α,25(OH)(2)D(3)-VDR promoted FBP1 expression to suppress glycolysis in γδ T cells, thereby inhibiting Akt/p38 MAPK phosphorylation and reducing inflammatory cytokine production. Notably, therapeutic administration of 1α,25(OH)(2)D(3) restrained inflammation in γδ T cells and ameliorated systemic insulin resistance in obese mice. Conclusions: Collectively, these findings show that 1α,25(OH)(2)D(3) plays an important role in maintaining γδ T cell homeostasis by orchestrating metabolic programs, and is a highly promising target for preventing obesity, inflammation, and insulin resistance.