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Biochemical, Molecular, and Genetic Mechanisms

Retinoids Upregulate Phosphoenolpyruvate Carboxykinase and Glyceroneogenesis in Human and Rodent Adipocytes^1,2

³ Institut National de la Recherche Médicale UMR-S 747, Université Paris Descartes, F-75006 Paris, France and ⁴ CNRS UMR 7079, Université Pierre et Marie Curie, F-75252 Paris, France

^* To whom correspondence should be addressed. E-mail: claude.forest{at}univ-paris5.fr.

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 (EC₅₀: 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 [1-¹⁴C]-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.