G3PP/PGP: A Novel Calorie Restriction Enzyme in C. Elegans

      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, we studied 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. Gro3P is a key metabolite that regulates flux of various metabolic pathways and particularly the glycerolipid/fatty acid (GL/FA) cycle associated with obesity, type 2 diabetes, and cardiometabolic disorders. We identify three homologues of Pgp in C. elegans (pgph-1, 2, 3) and demonstrate that they have G3PP activity and are essential for glycerol synthesis. Hyperosmotic and high glucose stresses induce pgph expression, glycerol production, and salt stress adaptation in a PGPH-dependent manner. Gro3P accumulates in pgph mutant animals in basal and more prominently following salt and glucose stresses, while other metabolites are largely unaltered. Using an unbiased transcription factors RNAi screen, we identify pgph-2 and pgph-3 salt-mediated transcriptional regulators. Loss of PGPH increases fat deposition and glucotoxicity and decreases resistance to various stresses, median lifespan and healthspan parameters. In contrast, pgph-2 overexpression reduces fat deposition without decreasing food intake or reproduction, protects from glucotoxicity and retards age-related locomotor decline in normal and high-glucose conditions. Our results demonstrate that G3PP/PGP is a novel evolutionary conserved regulator of glucose and fat metabolism that can be considered as a target for age related metabolic disorders.
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