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Identification of an Adipocyte-Specific Negative Glucose Response Region in the Cytosolic Aspartate Aminotransferase Gene¹

Centre de Recherche sur l’Endocrinologie Moléculaire et le Développement (E.P.-G., H.G., C.F.), Centre National de la Recherche Scientifique, 92190 Meudon, France; Institut National de la Santé et de la Recherche Médicale Unité 490 (M.A., F.B., R.B.), Centre Universitaire des Saints-Pères, 75006 Paris, France; Institut National de la Santé et de la Recherche Médicale Unité 129 (B.A.), Institute Cochin de Génétique Moléculaire, Centre Hospitalier Universitaire Cochin, 75014 Paris, France

Address all correspondence and requests for reprints to: Dr. Claude Forest, Centre de Recherche sur l’Endocrinologie Moléculaire et le Développement, CNRS, 9 rue Jules Hetzel, 92190 Meudon, France. E-mail: forest{at}cnrs-bellevue.fr

Cytosolic aspartate aminotransferase (cAspAT) participates in gluconeogenesis in the liver and is expected to exert a glyceroneogenic function in the adipose tissue when the supply of glucose is limited. Here we demonstrate that adipose cAspAT messenger RNA (mRNA) is increased when rats are fed a low carbohydrate diet. In the 3T3-F442A, BFC-1 adipocyte cell lines and differentiated adipocytes in primary culture, a 24 h glucose deprivation induces approximately a 4-fold increase in cytosolic AspAT (cAspAT) mRNA, whereas mitochondrial AspAT mRNA remains unchanged. cAspAT activity is also increased in a weaker but reproducible manner. Addition of glucose within a physiological range of concentrations reverses the increase of cAspAT mRNA in 8 h (EC₅₀ = 1.25 g/liter). Such a regulation requires protein synthesis and is specific for adipocytes differentiated in culture. It does not occur in Fao or H4IIE hepatoma cells, in C2 muscle cells, or in 293 kidney cells. 2-deoxyglucose mimicks glucose, while 3-orthomethyl-glucose has no effect, suggesting that glucose-6-phosphate is the effector. cAspAT mRNA stability is not affected by glucose deprivation. To ascertain the transcriptional nature of the glucose effect, we have stably transfected 3T3-F442A adipoblasts with constructs containing the chloramphenicol acetyltransferase reporter gene under the control of either 5'-deletions of the cAspAT gene promoter or internal fragments in an heterologous context. We demonstrate that a glucose response element(s) is present in the region between -1838 and -1702 bp relative to the translation start site. In this region, three DNA sequences bind nuclear proteins from adipocytes as shown by footprinting experiments. Our results indicate that cAspAT gene transcription is repressed by glucose selectively in adipocytes.

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