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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