Objective

Adipose tissue inflammation and fibrosis appear to contribute to insulin resistance in obesity. Vitamin D receptor (Vdr) genes are expressed by adipocytes, macrophages, and fibroblasts, all of which could potentially play a role in adipose tissue inflammation and fibrosis. As vitamin D has been shown to have direct anti-inflammatory effects on adipocytes, we determined whether specific vitamin D receptor-mediated effects on adipocytes could impact adipose tissue inflammation and fibrosis and ultimately insulin resistance.

Methods

We examined the effects of repleting vitamin D in 25(OH)D-deficient, insulin resistant, overweight-to-obese human subjects (n = 19). A comprehensive assessment of whole-body insulin action was undertaken with stepped euglycemic (∼90 mg/dL) hyperinsulinemic clamp studies both before and after the administration of vitamin D or placebo. Adipose tissue fibrosis and inflammation were quantified by real-time rt-PCR and immunofluorescence in subcutaneous abdominal adipose tissue.

To determine whether vitamin D's effects are mediated through adipocytes, we conducted hyperinsulinemic clamp studies (4 mU/kg/min) and adipose tissue analysis using an adipocyte-specific vitamin D receptor knockout (VDR-KO) mouse model (adiponectin-Cre + VDR+/fl) following high-fat diet feeding for 12 weeks.

Results

25(OH)D repletion was associated with reductions in adipose tissue expression of pro-inflammatory and pro-fibrotic genes, decreased collagen immunofluorescence, and improved hepatic insulin sensitivity in humans. Worsening trends after six months on placebo suggest progressive metabolic effects of 25(OH)D deficiency. Ad-VDR-KO mice mirrored the vitamin D-deficient humans, displaying increased adipose tissue fibrosis and inflammation and hepatic insulin resistance.

Conclusions

These complementary human and rodent studies support a beneficial role of vitamin D repletion for improving hepatic insulin resistance and reducing adipose tissue inflammation and fibrosis in targeted individuals, likely via direct effects on adipocytes. These studies have far-reaching implications for understanding the role of adipocytes in mediating adipose tissue inflammation and fibrosis and ultimately impacting insulin sensitivity.

中文翻译：

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由脂肪细胞维生素 D 受体介导的维生素 D 补充的胰岛素增敏作用：对人类和小鼠的研究

客观的

脂肪组织炎症和纤维化似乎有助于肥胖患者的胰岛素抵抗。维生素 D 受体 ( Vdr ) 基因由脂肪细胞、巨噬细胞和成纤维细胞表达，所有这些都可能在脂肪组织炎症和纤维化中发挥作用。由于维生素 D 已被证明对脂肪细胞具有直接抗炎作用，我们确定了特定的维生素 D 受体介导的对脂肪细胞的影响是否会影响脂肪组织炎症和纤维化，并最终影响胰岛素抵抗。

方法

我们检查了补充维生素 D 对缺乏 25(OH)D、胰岛素抵抗、超重到肥胖的人类受试者（n = 19）的影响。在服用维生素 D 或安慰剂之前和之后，通过阶梯式正常血糖 (~90 mg/dL) 高胰岛素钳夹研究对全身胰岛素作用进行了全面评估。脂肪组织纤维化和炎症通过皮下腹部脂肪组织中的实时 rt-PCR 和免疫荧光定量。

为了确定维生素 D 的作用是否通过脂肪细胞介导，我们使用脂肪细胞特异性维生素 D 受体敲除 (VDR-KO) 小鼠模型（脂联素-Cre + VDR+）进行了高胰岛素钳夹研究（4 mU/kg/min）和脂肪组织分析。 /fl) 高脂饮食喂养 12 周后。

结果

25(OH)D 的补充与脂肪组织中促炎和促纤维化基因的表达减少、胶原免疫荧光减少和人类肝脏胰岛素敏感性的提高有关。服用安慰剂 6 个月后的恶化趋势表明 25(OH)D 缺乏症的渐进性代谢影响。Ad-VDR-KO 小鼠反映了缺乏维生素 D 的人类，显示出增加的脂肪组织纤维化和炎症以及肝脏胰岛素抵抗。

结论

这些互补的人类和啮齿动物研究支持维生素 D 补充对改善肝脏胰岛素抵抗和减少目标个体的脂肪组织炎症和纤维化的有益作用，可能是通过对脂肪细胞的直接影响。这些研究对于理解脂肪细胞在介导脂肪组织炎症和纤维化以及最终影响胰岛素敏感性中的作用具有深远的意义。