缺乏共刺激受体 4-1BB 可预防肥胖引起的炎症和代谢紊乱。

OBJECTIVE

Inflammation is an important factor in the development of insulin resistance, type 2 diabetes, and fatty liver disease. As a member of the tumor necrosis factor receptor superfamily (TNFRSF9) expressed on immune cells, 4-1BB/CD137 provides a bidirectional inflammatory signal through binding to its ligand 4-1BBL. Both 4-1BB and 4-1BBL have been shown to play an important role in the pathogenesis of various inflammatory diseases.

RESEARCH DESIGN AND METHODS

Eight-week-old male 4-1BB-deficient and wild-type (WT) mice were fed a high-fat diet (HFD) or a regular diet for 9 weeks.

RESULTS

We demonstrate that 4-1BB deficiency protects against HFD-induced obesity, glucose intolerance, and fatty liver disease. The 4-1BB-deficient mice fed an HFD showed less body weight gain, adiposity, adipose infiltration of macrophages/T cells, and tissue levels of inflammatory cytokines (e.g., TNF-α, interleukin-6, and monocyte chemoattractant protein-1 [MCP-1]) compared with HFD-fed control mice. HFD-induced glucose intolerance/insulin resistance and fatty liver were also markedly attenuated in the 4-1BB-deficient mice.

CONCLUSIONS

These findings suggest that 4-1BB and 4-1BBL may be useful therapeutic targets for combating obesity-induced inflammation and metabolic disorders.

目的

炎症是胰岛素抵抗、2 型糖尿病和脂肪肝疾病发展的一个重要因素。作为肿瘤坏死因子受体超家族（TNFRSF9）的成员之一，表达于免疫细胞表面的 4-1BB/CD137 通过与其配体 4-1BBL 结合提供双向炎症信号。4-1BB 和 4-1BBL 均被证明在各种炎症性疾病的发病机制中发挥重要作用。

研究设计和方法

8 周龄雄性 4-1BB 缺陷型和野生型（WT）小鼠分别喂食高脂肪饮食（HFD）或普通饮食 9 周。

结果

我们证明 4-1BB 缺陷可预防 HFD 诱导的肥胖、葡萄糖不耐受和脂肪肝。与 HFD 喂养的对照组小鼠相比，喂食 HFD 的 4-1BB 缺陷型小鼠体重增加、肥胖、巨噬细胞/T 细胞脂肪浸润以及组织炎症细胞因子（如 TNF-α、白细胞介素-6 和单核细胞趋化蛋白-1 [MCP-1]）水平降低。HFD 诱导的葡萄糖不耐受/胰岛素抵抗和脂肪肝在 4-1BB 缺陷型小鼠中也明显减轻。