RESUMEN
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.
Asunto(s)
Adaptación Fisiológica/genética , Caenorhabditis elegans/genética , Glicerofosfatos/metabolismo , Proteínas del Helminto/genética , Longevidad/genética , Monoéster Fosfórico Hidrolasas/genética , Secuencia de Aminoácidos , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/crecimiento & desarrollo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Restricción Calórica , Ingestión de Alimentos/genética , Regulación de la Expresión Génica , Glucosa/metabolismo , Glucosa/farmacología , Glicerol/metabolismo , Glicerol-3-Fosfato O-Aciltransferasa/genética , Glicerol-3-Fosfato O-Aciltransferasa/metabolismo , Proteínas del Helminto/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Concentración Osmolar , Monoéster Fosfórico Hidrolasas/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Estrés Fisiológico/genéticaRESUMEN
BACKGROUND: The aim of the study is to compare the impact of intravenous glucose versus lipid versus saline on exercise-induced myocardial ischemia in patients with stable angina. METHODS: Twelve men with coronary artery disease and positive exercise tests performed a symptom-limited, modified Bruce electrocardiogram (ECG) exercise test at 3 sessions, 3 weeks apart. They randomly received, in double-blind design, at each session equal intravenous volumes of 10% glucose/insulin or Intralipid plus heparin or saline. We assessed the effects on (1) ischemic threshold (heart rate x systolic pressure at 1-mm ST-segment depression [STD]) and (2) maximum ST-depression (Max STD) corresponding to the highest heart rate x systolic pressure common to the 3 tests. RESULTS: During glucose infusion, glycemia increased from 5.7 +/- 0.4 to 9.4 +/- 3.0 mmol/L but did not change during lipid or saline infusion. During lipid infusion, free fatty acids increased from 0.32 +/- 0.19 to 1.44 +/- 0.46 mmol/L but decreased during glucose infusion from 0.39 +/- 0.21 to 0.04 +/- 0.03 mmol/L and did not change during saline. Exercise times were 10.0 +/- 3.4, 9.8 +/- 3.4, and 10.3 +/- 3.5 minutes, during glucose, lipid, and saline infusions, respectively. Ischemic thresholds (x 10(-3)) were 16.5 +/- 2.8, 16.8 +/- 2.7, and 16.6 +/- 2.6, respectively. MaxSTD was 2.5 +/- 1.4, 2.5 +/- 1.0, and 2.5 +/- 1.0 mm, respectively. CONCLUSION: Neither glucose-insulin nor lipid infusion modified exercise ischemic parameters compared with saline control, suggesting that marked and acute changes in exogenous energy substrate are unlikely to affect exercise-induced myocardial ischemia.
