Metabolomics

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Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans


ABSTRACT: Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here, we show that the overexpression of the C. elegans G3PP homolog, PGPH-2, decreases fat levels and mimics, in part, the beneficial effects of calorie restriction, particularly in glucotoxicity conditions, without reducing food intake. PGPH-2 overexpression depletes glycogen stores activating AMP-activate protein kinase, which leads to the HLH-30 nuclear translocation and activation of autophagy, promoting healthy aging. Transcriptomics reveal an HLH-30-dependent longevity and catabolic gene expression signature with PGPH-2 overexpression. Thus, G3PP overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and may be an attractive target for age-related metabolic disorders linked to excess nutrients.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase

SUBMITTER: Elite Possik 

PROVIDER: MTBLS6847 | MetaboLights | 2024-02-07

REPOSITORIES: MetaboLights

Dataset's files

Source:
Action DRS
MTBLS6847 Other
FILES Other
a_MTBLS6847_LC-MS_negative_reverse-phase_metabolite_profiling.txt Txt
i_Investigation.txt Txt
m_MTBLS6847_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv Tabular
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Publications

Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans.

Possik Elite E   Klein Laura-Lee LL   Sanjab Perla P   Zhu Ruyuan R   Côté Laurence L   Bai Ying Y   Zhang Dongwei D   Sun Howard H   Al-Mass Anfal A   Oppong Abel A   Ahmad Rasheed R   Parker Alex A   Madiraju S R Murthy SRM   Al-Mulla Fahd F   Prentki Marc M  

Nature communications 20230825 1


Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here  ...[more]

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