Thrombospondin-1 regulates adiposity and metabolic dysfunction in diet-induced obesity enhancing adipose inflammation and stimulating adipocyte proliferation
Thrombospondin-1 regulates adiposity and metabolic dysfunction in diet-induced obesity enhancing adipose inflammation and stimulating adipocyte proliferation
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DOI：
10.1152/ajpendo.00006.2013
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发表时间：
2013-08-01
影响因子：
5.1
通讯作者：
Frangogiannis, Nikolaos G.
中科院分区：
文献类型：
--
作者：
Kong, Ping;Gonzalez-Quesada, Carlos;Frangogiannis, Nikolaos G.
作为一种典型的基质细胞蛋白，血小板反应蛋白 (TSP)-1 与结构基质结合，并通过调节生长因子和细胞因子信号传导来调节细胞行为。肥胖和糖尿病与脂肪组织中 TSP-1 的显着上调有关。我们假设内源性 TSP-1 可能在饮食引起的肥胖和代谢功能障碍的发病机制中发挥重要作用。因此，我们研究了 TSP-1 基因破坏对接受高脂肪饮食（HFD：60% 脂肪，20% 碳水化合物）或高碳水化合物低脂饮食（HCLFD：10% 脂肪，70% 碳水化合物）的小鼠的体重增加、肥胖和脂肪组织炎症的影响。 HFD 小鼠的性腺周围脂肪组织中 TSP-1 表达显着升高； TSP-1 主要位于脂肪间质中。 TSP-1 的损失减弱了 HFD 和 HCLFD 组的体重增加和脂肪积累。与相应的野生型动物相比，TSP-1缺失小鼠的胰岛素水平降低，但游离脂肪酸和甘油三酯水平升高，表明脂肪酸摄取受损。 TSP-1 损失不影响脂肪细胞大小，也不影响脂肪血管密度。然而，TSP-1缺失小鼠表现出肿瘤坏死因子-α mRNA表达减弱和巨噬细胞浸润减少，表明TSP-1在介导肥胖相关炎症中发挥作用。在体外，TSP-1 增强 3T3-L1 前脂肪细胞的增殖，但不调节炎症细胞因子和趋化因子的合成。总之，TSP-1 上调有助于体重增加、脂肪生长和代谢功能障碍的发病机制。 TSP-1 的作用可能涉及刺激脂肪细胞增殖、激活炎症信号传导以及促进脂肪细胞摄取脂肪酸。
As a typical matricellular protein, thrombospondin (TSP)-1, binds to the structural matrix and regulates cellular behavior by modulating growth factor and cytokine signaling. Obesity and diabetes are associated with marked upregulation of TSP-1 in adipose tissue. We hypothesized that endogenous TSP-1 may play an important role in the pathogenesis of diet-induced obesity and metabolic dysfunction. Accordingly, we examined the effects of TSP-1 gene disruption on weight gain, adiposity, and adipose tissue inflammation in mice receiving a high-fat diet (HFD: 60% fat, 20% carbohydrate) or a high-carbohydrate low-fat diet (HCLFD: 10% fat, 70% carbohydrate). HFD mice had significantly higher TSP-1 expression in perigonadal adipose tissue; TSP-1 was predominantly localized in the adipose interstitium. TSP-1 loss attenuated weight gain and fat accumulation in HFD and HCLFD groups. Compared with corresponding wild-type animals, TSP-1-null mice had decreased insulin levels but exhibited elevated free fatty acid and triglyceride levels, suggesting impaired fatty acid uptake. TSP-1 loss did not affect adipocyte size and had no effect on adipose vascular density. However, TSP-1-null mice exhibited attenuated tumor necrosis factor-alpha mRNA expression and reduced macrophage infiltration, suggesting a role for TSP-1 in mediating obesity-associated inflammation. In vitro, TSP-1 enhanced proliferation of 3T3-L1 preadipocytes but did not modulate inflammatory cytokine and chemokine synthesis. In conclusion, TSP-1 upregulation contributes to weight gain, adipose growth, and the pathogenesis of metabolic dysfunction. The effects of TSP-1 may involve stimulation of adipocyte proliferation, activation of inflammatory signaling, and facilitated fatty acid uptake by adipocytes.