Vitamin D against diabetic adipose tissue inflammation through SHP-1/STAT3 pathway

Purpose: This study aimed to investigate the anti-inflammatory effects of vitamin D (VD) on adipose tissue in type 2 diabetes mellitus (T2DM), with a particular focus on its regulation of macrophage polarization and the SHP-1/STAT3 signaling pathway. Methods: A T2DM rat model was induced in 4-week-old Sprague-Dawley rats by feeding a high-fat diet followed by a low-dose streptozotocin injection. After successful model induction, the diabetic rats were treated with varying doses of vitamin D3 (VD3) for 10 weeks to evaluate its effects on adipose tissue inflammation associated with T2DM. To further elucidate the underlying mechanisms, high-glucose (HG)-stimulated RAW264.7 macrophages were employed as an in vitro model to investigate the anti-inflammatory effects of 1,25(OH)(2)D-3, with particular emphasis on the SHP-1/STAT3 signaling pathway. Results: VD3 treatment significantly improved body weight, reduced water intake and urine output, and alleviated hyperglycemia and dyslipidemia in T2DM rats (P < 0.05). Histological analysis revealed restored adipocyte morphology and reduced expression of inflammatory cytokines (TNF-alpha, IL-6, TGF-beta 1, MCP-1; P < 0.05). Immunofluorescence and protein analyses demonstrated that VD3 inhibited M1 macrophage polarization and enhanced the M2 phenotype. Moreover, VD3 upregulated SHP-1 expression while downregulating p-STAT3 in adipose tissue (P < 0.05). In vitro, 1,25(OH)(2)D-3 restored cell viability, suppressed pro-inflammatory cytokine production, and promoted M2 polarization under HG conditions (P < 0.05). Inhibition of SHP-1 using TPI-1 abrogated these effects, whereas STAT3 inhibition with stattic further enhanced the anti-inflammatory responses (P < 0.05). Conclusion: VD mitigates adipose tissue inflammation and metabolic dysfunction in T2DM by regulating macrophage polarization via the SHP-1/STAT3 signaling pathway.