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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213910 | GEO | 2025/09/20

REPOSITORIES: GEO

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Project description:Fibroblast growth factor 23 (FGF23) is produced and secreted by osteocytes and is essential for maintaining phosphate homeostasis. One of the main regulators of FGF23, 1,25-dihydroxyvitamin D (1,25(OH)2D3), is primarily synthesized in the kidney from 25-hydroxyvitamin D (25(OH)D) by 1α-hydroxylase (encoded by CYP27B1). Hitherto, it is unclear whether osteocytes can convert 25(OH)D and thereby allow for 1,25(OH)2D3 to induce FGF23 production and secretion locally. Here, we differentiated MC3T3-E1 cells towards osteocyte-like cells expressing and secreting FGF23. Treatment with 10-6 M 25(OH)D resulted in conversion of 25(OH)D to 150 pmol/L 1,25(OH)2D3 and increased FGF23 expression and secretion but the converted amount of 1,25(OH)2D3 was insufficient to trigger an FGF23 response, so the effect on FGF23 was most likely directly caused by 25(OH)D. Interestingly, combining phosphate with 25(OH)D resulted in a synergistic increase in FGF23 expression and secretion, likely due to activation of additional signaling pathways by phosphate. Blockage of the vitamin D receptor (VDR) only partially abolished the effects of 25(OH)D or 25(OH)D combined with phosphate on Fgf23, while completely inhibiting the upregulation of cytochrome P450 family 24 subfamily A member 1 (Cyp24a1), encoding for 24-hydroxylase. RNA sequencing and in silico analyses showed that this could potentially be mediated by the nuclear receptors Retinoic Acid Receptor b (RARB) and Estrogen Receptor 2 (ESR2). Taken together, we demonstrate that osteocytes are able to convert 25(OH)D to 1,25(OH)2D3, but this is insufficient for FGF23 activation, implicating a direct effect of 25(OH)D in the regulation of FGF23, which occurs at least partially independent from its cognate vitamin D receptor Moreover, phosphate and 25(OH)D synergistically increase expression and secretion of FGF23, which warrants investigating consequences in patients receiving a combination of vitamin D analogues and phosphate supplements. These observations help us to further understand the complex relations between, phosphate, vitamin D and FGF23.

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

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