title: Retinoids upregulate phosphoenolpyruvate carboxykinase and glyceroneogenesis in human and rodent adipocytes.
abstract: Glyceroneogenesis is an important metabolic pathway for fatty acid reesterification in adipose tissue, thereby reducing fatty acid release. Glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), which is the key enzyme in this pathway, are both regulated by a series of hormones and nutrients, among which all-trans retinoic acid (all-trans RA) is a transcriptional inducer of the PEPCK-C gene (Pck1). All-trans RA binds to the retinoic acid receptor (RAR) and activates it, whereas its stereoisomer 9-cis retinoic acid (9-cis RA) is a ligand for the 9-cis RA receptor (RXR). Three RXR-binding elements [retinoic acid response element (RARE)1/PCK1, RARE2, and RARE3/PCK2] were previously located in the promoter of Pck1. Using 3T3-F442A adipocytes, we demonstrated that Pck1 expression was 10-fold more sensitive to 9-cis RA (EC(50): 10 nmol/L) than to all-trans RA. We then analyzed the respective involvement of RARE1/PCK1, RARE2, and RARE3/PCK2 in the response of Pck1 to 9-cis RA and all-trans RA in adipocytes. The response to 9-cis RA mainly involved the RARE1/PCK1 element, whereas RARE2 was mainly responsive to all-trans RA. In contrast, the full response to both RA isomers involved these 2 elements and included RARE3/PCK2 as well. Furthermore, 9-cis RA, but not all-trans RA, selectively induced PCK1 in ex-vivo-treated human adipose tissue explants, with a concomitant induction of glyceroneogenesis monitored by [1-(14)C]-pyruvate incorporation into neutral lipids. The concomitant 9-cis RA-induced reduction in fatty acid output indicates an important role for this RA stereoisomer in lipid homeostasis through stimulation of PEPCK-C and glyceroneogenesis in adipose tissue.
authors.affiliation: Institut National de la Recherche Médicale UMR-S 747, Université Paris Descartes, F-75006 Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cadoudal
authors.forename: Martine
authors.initials: M
authors.lastname: Glorian
authors.forename: Aurélie
authors.initials: A
authors.lastname: Massias
authors.forename: Françoise
authors.initials: F
authors.lastname: Fouque
authors.forename: Claude
authors.initials: C
authors.lastname: Forest
authors.forename: Chantal
authors.initials: C
authors.lastname: Benelli
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D052436:Adipose Tissue, White / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005990:Glycerol / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D009154:Mutation; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D012176:Retinoids; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005990:Glycerol