Wei Xiaonuo, Wang Yulin, Liu Wenyi, Zhang Dongdong, Zhou Chunyu, Jiang Zhongyan, Li Wenjie, Li Xing, Miao Yufan
Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, China.
The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China.
Int Immunopharmacol. 2025 Jun 23;162:115131. doi: 10.1016/j.intimp.2025.115131.
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.
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)D, with particular emphasis on the SHP-1/STAT3 signaling pathway.
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-α, IL-6, TGF-β1, 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)D 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).
VD mitigates adipose tissue inflammation and metabolic dysfunction in T2DM by regulating macrophage polarization via the SHP-1/STAT3 signaling pathway.
本研究旨在探讨维生素D（VD）对2型糖尿病（T2DM）患者脂肪组织的抗炎作用，特别关注其对巨噬细胞极化和SHP-1/STAT3信号通路的调节。
通过高脂饮食喂养4周龄的Sprague-Dawley大鼠，随后注射低剂量链脲佐菌素，诱导建立T2DM大鼠模型。成功诱导模型后，用不同剂量的维生素D3（VD3）治疗糖尿病大鼠10周，以评估其对T2DM相关脂肪组织炎症的影响。为进一步阐明潜在机制，采用高糖（HG）刺激的RAW264.7巨噬细胞作为体外模型，研究1,25(OH)D的抗炎作用，特别关注SHP-1/STAT3信号通路。
VD3治疗显著改善了T2DM大鼠的体重，减少了水摄入量和尿量，缓解了高血糖和血脂异常（P < 0.05）。组织学分析显示脂肪细胞形态恢复，炎症细胞因子（TNF-α、IL-6、TGF-β1、MCP-1）表达降低（P < 0.05）。免疫荧光和蛋白质分析表明，VD3抑制M1巨噬细胞极化并增强M2表型。此外，VD3上调脂肪组织中SHP-1的表达，同时下调p-STAT3（P < 0.05）。在体外，1,25(OH)D在HG条件下恢复细胞活力，抑制促炎细胞因子产生，并促进M2极化（P < 0.05）。使用TPI-1抑制SHP-1可消除这些作用，而用stattic抑制STAT3则进一步增强抗炎反应（P < 0.05）。
VD通过SHP-1/STAT3信号通路调节巨噬细胞极化，减轻T2DM患者的脂肪组织炎症和代谢功能障碍。
