Rasal2 deficiency reduces adipogenesis and occurrence of obesity-related disorders.
Rasal2 deficiency reduces adipogenesis and occurrence of obesity-related disorders.
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Rasal2 缺乏会减少脂肪生成和肥胖相关疾病的发生
DOI：
10.1016/j.molmet.2017.03.003
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发表时间：
2017-06
影响因子：
8.1
通讯作者：
Han M
中科院分区：
文献类型：
--
作者：
Zhu X;Xie S;Xu T;Wu X;Han M
识别与肥胖发病有关的其他调节因素对于了解这种流行疾病及其相关代谢紊乱的机制以及制定治疗策略非常重要。通过对突变体的分离和分析，我们的目的是揭示 Ras-GAP 基因 Rasal2（Ras 蛋白激活剂样 2）在肥胖和相关代谢紊乱发展中的功能，并获得有关该功能背后机制的宝贵见解。进行了基于肥胖的遗传筛查，以确定破坏 Rasal2 表达的插入突变（Rasal2PB/PB 小鼠）。在 Rasal2PB/PB 小鼠中测量了重要的代谢参数，例如脂肪量和葡萄糖耐量。在突变小鼠和用 Rasal2 siRNA 处理的 3T3-L1 前脂肪细胞中评估 Rasal2 对脂肪生成的影响。然后在 Rasal2 缺陷的前脂肪细胞或小鼠中评估 Ras 和 ERK 活性，并通过使用 Ras 和 MEK 抑制剂研究它们与 Rasal2 对脂肪生成的功能关系。 Rasal2PB/PB 小鼠表现出 Rasal2 表达急剧下降和瘦表型。突变小鼠表现出肥胖减少和对高脂肪饮食引起的代谢紊乱的抵抗力。进一步的分析表明 Rasal2 缺陷会导致体内和体外脂肪生成受损。此外，虽然Rasal2缺陷导致前脂肪细胞中Ras和ERK的活性增加，但Ras的减少，而不是ERK的减少，抑制了受损的脂肪生成。 Rasal2 促进脂肪生成，这可能对其在肥胖和相关代谢紊乱的发展中发挥重要作用，并且可能通过以不依赖于 ERK 的方式抑制 Ras 活性来实现这一作用。 Rasal2缺陷型小鼠无论喂食高脂肪饮食还是正常饮食，其肥胖程度均有所降低。 Rasal2缺陷小鼠对高脂饮食引起的肥胖和相关代谢紊乱具有抵抗力。 Rasal2 缺乏会导致体内和体外脂肪生成减少。 Rasal2 可能通过不依赖于 ERK 的机制抑制 Ras 活性来调节脂肪生成。
Identification of additional regulatory factors involved in the onset of obesity is important to understand the mechanisms underlying this prevailing disease and its associated metabolic disorders and to develop therapeutic strategies. Through isolation and analysis of a mutant, we aimed to uncover the function of a Ras-GAP gene, Rasal2 (Ras protein activator like 2), in the development of obesity and related metabolic disorders and to obtain valuable insights regarding the mechanism underlying the function. An obesity-based genetic screen was performed to identify an insertional mutation that disrupts the expression of Rasal2 (Rasal2PB/PB mice). Important metabolic parameters, such as fat mass and glucose tolerance, were measured in Rasal2PB/PB mice. The impact of Rasal2 on adipogenesis was evaluated in the mutant mice and in 3T3-L1 preadipocytes treated with Rasal2 siRNA. Ras and ERK activities were then evaluated in Rasal2-deficient preadipocytes or mice, and their functional relationships with Rasal2 on adipogenesis were investigated by employing Ras and MEK inhibitors. Rasal2PB/PB mice showed drastic decrease in Rasal2 expression and a lean phenotype. The mutant mice displayed decreased adiposity and resistance to high-fat diet induced metabolic disorders. Further analysis indicated that Rasal2 deficiency leads to impaired adipogenesis in vivo and in vitro. Moreover, while Rasal2 deficiency resulted in increased activity of both Ras and ERK in preadipocytes, reducing Ras, but not ERK, suppressed the impaired adipogenesis. Rasal2 promotes adipogenesis, which may critically contribute to its role in the development of obesity and related metabolic disorders and may do so by repressing Ras activity in an ERK-independent manner. Rasal2-deficient mice show decreased adiposity fed on either high-fat or normal-chow diet. Rasal2-deficient mice are resistant to high-fat diet-induced obesity and related metabolic disorders. Rasal2 deficiency causes a decrease in adipogenesis in vivo and in vitro. Rasal2 likely regulates adipogenesis by repressing Ras activity through an ERK-independent mechanism.