Department of Nutrition, Université de Montréal, Montreal Diabetes Research Center, CRCHUM, Montréal, Canada.
Department of Biochemistry and Molecular Medicine, Montreal Diabetes Research Center, CRCHUM, Montréal, Canada.
Nat Commun. 2022 Jan 11;13(1):177. doi: 10.1038/s41467-021-27803-6.
Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we study the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol-3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol. We identify three Pgp homologues in C. elegans (pgph) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis. We demonstrate that PGPH/G3PP regulates the adaptation to various stresses, in particular hyperosmolarity and glucotoxicity. Enhanced G3PP activity reduces fat accumulation, promotes healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility. Thus, PGP/G3PP can be considered as a target for age-related metabolic disorders.
营养过剩和脂质积累导致的代谢应激是许多与年龄相关的疾病的根源，因此鉴定出能够模拟卡路里限制有益效果的治疗靶点具有重要的临床意义。在这里，我们使用秀丽隐杆线虫作为模式生物，研究了一种最近在哺乳动物细胞中发现的代谢核心酶——甘油-3-磷酸磷酸酶（G3PP）（基因名称 Pgp）的作用，该酶将葡萄糖衍生的甘油-3-磷酸水解为甘油。我们在秀丽隐杆线虫中鉴定出三个 Pgp 同源物（pgph），并证明其蛋白质产物具有 G3PP 活性，这对于甘油合成至关重要。我们证明 PGPH/G3PP 调节对各种应激的适应，特别是高渗应激和糖毒性。增强的 G3PP 活性可减少脂肪积累，促进健康衰老，并在正常进食的情况下模拟卡路里限制，而不影响生育能力。因此，PGP/G3PP 可以被认为是与年龄相关的代谢紊乱的一个靶点。
