State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
Howard Hughes Medical Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
Mol Metab. 2017 Mar 18;6(6):494-502. doi: 10.1016/j.molmet.2017.03.003. eCollection 2017 Jun.
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 ( mice). Important metabolic parameters, such as fat mass and glucose tolerance, were measured in 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.
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 and 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.
鉴定肥胖发生过程中涉及的其他调节因子对于理解这种普遍疾病及其相关代谢紊乱的发病机制，以及开发治疗策略非常重要。通过分离和分析突变体，我们旨在揭示 Ras-GAP 基因 Rasal2（Ras 蛋白激活物样 2）在肥胖和相关代谢紊乱发展中的功能，并深入了解其功能的作用机制。
进行基于肥胖的遗传筛选，以鉴定破坏 Rasal2 表达的插入突变（mice）。在 mice 中测量重要的代谢参数，如脂肪量和葡萄糖耐量。在突变小鼠和用 Rasal2 siRNA 处理的 3T3-L1 前体脂肪细胞中评估 Rasal2 对脂肪生成的影响。然后评估 Rasal2 缺陷前体脂肪细胞或 mice 中的 Ras 和 ERK 活性，并通过使用 Ras 和 MEK 抑制剂研究它们与 Rasal2 在脂肪生成上的功能关系。
mice 表现出 Rasal2 表达的急剧下降和瘦表型。突变小鼠表现出脂肪量减少和对高脂肪饮食诱导的代谢紊乱的抗性。进一步分析表明，Rasal2 缺乏导致脂肪生成受损，而且，虽然 Rasal2 缺乏导致前体脂肪细胞中 Ras 和 ERK 的活性增加，但减少 Ras（而非 ERK）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发展中的作用至关重要，并且可能通过以 ERK 独立的方式抑制 Ras 活性来实现。
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