Translocator protein (18 kDa) as a pharmacological target in adipocytes to regulate glucose homeostasis
Translocator protein (18 kDa) as a pharmacological target in adipocytes to regulate glucose homeostasis
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DOI：
10.1016/j.bcp.2015.06.020
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发表时间：
2015-09-01
影响因子：
5.8
通讯作者：
Papadopoulos, Vassilios
中科院分区：
文献类型：
--
作者：
Li, Jiehan;Papadopoulos, Vassilios
作为肥胖及其相关代谢并发症的主要调节因子，脂肪细胞的正常功能对于维持健康至关重要，因此成为抗肥胖和抗糖尿病疗法开发的重要目标。越来越多的证据表明，线粒体功能障碍是一个关键事件，在干扰脂肪细胞的细胞内稳态。在主要的线粒体结构组分中，高亲和力的药物和胆固醇结合的线粒体外膜转运蛋白（18 kDa; TSPO）在广泛的线粒体功能中显示出重要性。最近的研究表明TSPO存在于小鼠的白色脂肪细胞线粒体中，并且向肥胖小鼠施用TSPO药物配体减少了体重增加并降低了葡萄糖水平。因此，评估脂肪细胞中的TSPO是否可以作为调节脂肪细胞活性的药物靶标，对体重控制和葡萄糖代谢具有潜在影响，是非常有趣的。两种结构不同的TSPO药物配体PK 11195和FGIN-1-27改善了3 T3-L1脂肪细胞的细胞内动力学，例如脂肪因子的产生和释放、葡萄糖摄取和脂肪生成。在分化的脂肪细胞或前脂肪细胞中TSPO敲低损害了这些功能。来自3 T3-L1细胞的发现与人原代细胞相关，其中TSPO表达与原代脂肪细胞的代谢状态和原代前脂肪细胞的分化密切相关。这些结果表明，TSPO的表达是必不可少的，以保障健康的脂肪细胞的功能，和TSPO在脂肪细胞中的活化改善其代谢状态，在调节葡萄糖稳态。脂肪细胞TSPO可作为治疗肥胖和糖尿病的药理学靶点。(C)2015 Elsevier Inc. All rights reserved.
As a major regulator in obesity and its associated metabolic complications, the proper functioning of adipocytes is crucial for health maintenance, thus serving as an important target for the development of anti-obese and anti-diabetic therapies. There is increasing evidence that mitochondrial malfunction is a pivotal event in disturbing adipocyte cell homeostasis. Among major mitochondrial structure components, the high-affinity drug- and cholesterol-binding outer mitochondrial membrane translocator protein (18 kDa; TSPO) has shown importance across a broad spectrum of mitochondrial functions. Recent studies demonstrated the presence of TSPO in white adipocyte mitochondria of mice, and administration of TSPO drug ligands to obese mice reduced weight gain and lowered glucose level. Therefore, it is of great interest to assess whether TSPO in adipocytes could serve as a drug target to regulate adipocyte activities with potential influence on weight control and glucose metabolism. Two structurally distinct TSPO drug ligands, PK 11195 and FGIN-1-27, improved the intracellular dynamics of 3T3-L1 adipocytes, such as the production and release of adipokines, glucose uptake, and adipogenesis. TSPO knockdown in either differentiated adipocytes or preadipocytes impaired these functions. Findings from 3T3-L1 cells were related to human primary cells, where TSPO expression was tightly associated with the metabolic state of primary adipocytes and the differentiation of primary preadipocytes. These results suggest that TSPO expression is essential to safeguard healthy adipocyte functions, and that TSPO activation in adipocytes improves their metabolic status in regulating glucose homeostasis. Adipocyte TSPO may serve as a pharmacologic target for the treatment of obesity and diabetes. (C) 2015 Elsevier Inc. All rights reserved.