Rapid nitration of adipocyte phosphoenolpyruvate carboxykinase by leptin reduces glyceroneogenesis and induces fatty acid release.
Fatty acid (FA) release from white adipose tissue (WAT) is the result of the balance between triglyceride breakdown and FA re-esterification. The latter relies on the induction of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), the key enzyme for glyceroneogenesis. We previously demonstrated that long-term (18 h) leptin treatment of rat epididymal WAT explants reduced glyceroneogenesis through nitric oxide (NO)-induced decrease in PEPCK-C expression. We investigated the effect of a short-term leptin treatment (2 h) on PEPCK-C expression and glyceroneogenesis in relation to NO production. We demonstrate that in WAT explants, leptin-induced NO synthase III (NOS III) phosphorylation was associated with reduced PEPCK-C level and glyceroneogenesis, leading to FA release, while PEPCK-C gene expression remained unaffected. These effects were absent in WAT explants from leptin receptor-deficient Zucker rat. Immunoprecipitation and western blot experiments showed that the leptin-induced decrease in PEPCK-C level was correlated with an increase in PEPCK-C nitration. All these effects were abolished by the NOS inhibitor Nω-nitro-L-arginine methyl ester and mimicked by the NO donor S-nitroso-N-acetyl-DL penicillamine. We propose a mechanism in which leptin activates NOS III and induces NO that nitrates PEPCK-C to reduce its level and glyceroneogenesis, therefore limiting FA re-esterification in WAT.
Institut National de la Santé et de la Recherche Médicale UMR-S 747, Université Paris Descartes, Pharmacologie Toxicologie et Signalisation Cellulaire, Paris, France.
Anne-Marie
AM
Jaubert
Graziella
G
Penot
Fatoumata
F
Niang
Sylvie
S
Durant
Claude
C
Forest
D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005990:Glycerol / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D020738:Leptin / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
D005227:Fatty Acids; D020738:Leptin; D012333:RNA, Messenger; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005990:Glycerol; D019331:NG-Nitroarginine Methyl Ester