《細胞-代謝》(Cell Metabolism)雜志近日發(fā)表了中科院上海生科院營養(yǎng)科學(xué)研究所劉勇研究組和中科院海外糖尿病研究團隊成員-美國密歇根大學(xué)芮良優(yōu)教授的最新合作研究成果,揭示了信號接頭蛋白SH2B1對生長發(fā)育,、糖脂代謝和壽命的調(diào)控作用和機制,,提示從低等動物果蠅到哺乳動物小鼠的進化中SH2B在特定調(diào)節(jié)功能上具有保守性,。
SH2B是一類含有SH2(Src homology 2)和PH(pleckstrin homology)結(jié)構(gòu)域的信號接頭蛋白(Adaptor),,在生長發(fā)育、代謝平衡和免疫調(diào)節(jié)等多方面發(fā)揮重要的調(diào)控作用,。在哺乳動物中,,SH2B家族成員SH2B1能夠促進脂肪因子瘦素在中樞神經(jīng)系統(tǒng)中的信號轉(zhuǎn)導(dǎo)功能,,是體重調(diào)節(jié)的重要調(diào)控因子,。最近人類全基因組掃描研究表明,SH2B1與肥胖和2型糖尿病的發(fā)生密切相關(guān),。
為深入探討SH2B的代謝調(diào)控機制在分子功能上的進化特征,,劉勇研究組博士生宋威等在芮良優(yōu)教授和李文君博士的指導(dǎo)下,通過一系列生理學(xué)和遺傳學(xué)研究手段,,發(fā)現(xiàn)SH2B1在果蠅的同源蛋白dSH2B能通過與Chico(果蠅中胰島素受體底物IRS的同源蛋白)相互作用,,直接提升果蠅體內(nèi)的胰島素信號轉(zhuǎn)導(dǎo)能力。果蠅體內(nèi)dSH2B基因的缺失會減弱胰島素信號轉(zhuǎn)導(dǎo),、減緩生長發(fā)育,,同時隨著淋巴液中葡萄糖水平與全身脂肪含量的升高,機體對饑餓與氧化應(yīng)激產(chǎn)生抵抗,,進而導(dǎo)致果蠅壽命的延長,;而在果蠅全身過表達dSH2B則呈現(xiàn)完全相反的表型,。進一步研究發(fā)現(xiàn),在果蠅的脂肪體(功能上相當(dāng)于哺乳動物的肝臟和脂肪組織)中過表達dSH2B能降低糖脂水平,;而在果蠅神經(jīng)元中過表達dSH2B則使果蠅對氧化應(yīng)激更為敏感,,并導(dǎo)致壽命的縮短。與此對應(yīng),,芮良優(yōu)研究組則發(fā)現(xiàn)SH2B1基因缺失的小鼠同樣呈現(xiàn)生長緩慢,、肥胖和2型糖尿病的癥狀;但與果蠅不同的是,,SH2B1缺失使小鼠對氧化應(yīng)激更為敏感,、而且導(dǎo)致壽命的縮短。這些研究結(jié)果表明,,從進化上講SH2B對胰島素信號轉(zhuǎn)導(dǎo),、生長與代謝的調(diào)控具有高度的功能保守性,而在氧化應(yīng)激與壽命的調(diào)控方面則發(fā)生了功能上的進化演變,。
這項研究利用簡單,、成熟的果蠅遺傳學(xué)模型,通過研究機體生長,、代謝和壽命的分子調(diào)節(jié)機制及其在功能進化上的保守特征,,為深入了解重大代謝疾病發(fā)生發(fā)展的生理學(xué)機制,進一步闡明生長發(fā)育,、代謝以及衰老和壽命等重要生命活動的生物學(xué)基礎(chǔ)提供了重要的線索,。
該項工作得到了國家自然科學(xué)基金委(包括海外杰青B類)、國家科技部,、中科院(糖尿病海外研究團隊)和上海市科委(啟明星人才計劃)的基金支持,。研究期間還得到上海生科院神經(jīng)所黃福德研究員與果蠅研究平臺、植生生態(tài)所李勝研究員等各方面的大力合作與支持,。(生物谷Bioon.com)
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生物谷推薦原文出處:
Cell Metabolism DOI:10.1016/j.cmet.2010.04.002
SH2B Regulation of Growth, Metabolism, and Longevity in Both Insects and Mammals
Wei Song, Decheng Ren, Wenjun Li, Lin Jiang, Kae Won Cho, Ping Huang, Chen Fan, Yiyun Song, Yong Liu, Liangyou Rui
SH2B1 is a key regulator of body weight in mammals. Here, we identified dSH2B as the Drosophila homolog of SH2B1. dSH2B bound to Chico and directly promoted insulin-like signaling. Disruption of dSH2B decreased insulin-like signaling and somatic growth in flies. dSH2B deficiency also increased hemolymph carbohydrate levels, whole-body lipid levels, life span, and resistance to starvation and oxidative stress. Systemic overexpression of dSH2B resulted in opposite phenotypes. dSH2B overexpression in fat body decreased lipid and glucose levels, whereas neuron-specific overexpression of dSH2B decreased oxidative resistance and life span. Genetic deletion of SH2B1 also resulted in growth retardation, obesity, and type 2 diabetes in mice; surprisingly, life span and oxidative resistance were reduced in SH2B1 null mice. These data suggest that dSH2B regulation of insulin-like signaling, growth, and metabolism is conserved in SH2B1, whereas dSH2B regulation of oxidative stress and longevity may be conserved in other SH2B family members.
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China Department of Molecular and Integrative Physiology, the University of Michigan Medical School, Ann Arbor, MI 48109, USA Corresponding author These authors contributed equally to this work