Abstract
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.
Highlights
Metabolic stress due to nutrient excess and lipid accumulation is at the root of many ageassociated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance
We demonstrate that the worm PGPH acts as a Gro3P phosphatase in vivo and that glycerol-3-phosphate phosphatase (G3PP) is involved in the response to various stresses, including excess glucose and hyperosmotic stress, as well as healthy aging
We show that enhanced PGPH/G3PP activity reduces fat accumulation and in part mimics the beneficial effects of dietary restriction and promotes healthy aging, in conditions of excess glucose, without adversely affecting the apparent food intake or reproduction
Summary
Metabolic stress due to nutrient excess and lipid accumulation is at the root of many ageassociated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. 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. Glycerolipid/free fatty acid (GL/FFA) cycle links lipid and glucose metabolism and its dysregulation is associated with metabolic and age-related diseases[1,2]. This cycle, consisting of its lipogenesis and lipolysis arms, generates signaling molecules and promotes thermogenesis. The physiological relevance of these activities remains to be defined in vivo, as the cellular concentrations of these metabolites are very low under normal culture conditions[5]
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