Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor
Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor
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DOI：
10.1073/pnas.1512156113
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发表时间：
2016-08-09
影响因子：
11.1
通讯作者：
Gruenbaum, Yosef
中科院分区：
文献类型：
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作者：
Bar, Daniel Z.;Charar, Chayki;Gruenbaum, Yosef
饮食限制（DR）是一种代谢干预措施，可以延长多种物种的寿命，包括酵母、苍蝇、线虫、啮齿动物，甚至恒河猴和人类。终生 DR 的标志是体型、生育力和脂肪积累的减少，以及发育减慢。我们已经鉴定出 atx-2（人类 ATXN2L 和 ATXN2 基因的秀丽隐杆线虫同源物）是这些多种 DR 表型的调节因子。 atx-2 的下调会增加饮食限制动物的体型、细胞大小和脂肪含量，并加速动物发育，而 atx-2 的过度表达足以减少野生型动物的体型和窝体大小。 atx-2 通过与 Rab GDP 解离抑制剂 β 直接相关，调节 rapamycin (mTOR) 通路的机制靶标、AMP 激活蛋白激酶 (AMPK) 的下游以及核糖体蛋白 S6 激酶和 mTOR 复合物 1 (TORC1) 的上游，该抑制剂可能调节 RHEB 在 GDP 结合型和 GTP 结合型之间穿梭。总而言之，这项工作确定了一种以前未知的调节 DR 多个方面的机制，以及 mTOR 通路的未知调节因子。它们还扩展了我们对饮食依赖性生长迟缓的理解，并提供了治疗肥胖的潜在机制。
Dietary restriction (DR) is a metabolic intervention that extends the lifespan of multiple species, including yeast, flies, nematodes, rodents, and, arguably, rhesus monkeys and humans. Hallmarks of lifelong DR are reductions in body size, fecundity, and fat accumulation, as well as slower development. We have identified atx-2, the Caenorhabditis elegans homolog of the human ATXN2L and ATXN2 genes, as the regulator of these multiple DR phenotypes. Down-regulation of atx-2 increases the body size, cell size, and fat content of dietary-restricted animals and speeds animal development, whereas overexpression of atx-2 is sufficient to reduce the body size and brood size of wild-type animals. atx-2 regulates the mechanistic target of rapamycin (mTOR) pathway, downstream of AMP-activated protein kinase (AMPK) and upstream of ribosomal protein S6 kinase and mTOR complex 1 (TORC1), by its direct association with Rab GDP dissociation inhibitor beta, which likely regulates RHEB shuttling between GDP-bound and GTP-bound forms. Taken together, this work identifies a previously unknown mechanism regulating multiple aspects of DR, as well as unknown regulators of the mTOR pathway. They also extend our understanding of diet-dependent growth retardation, and offers a potential mechanism to treat obesity.