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Overexpression of ₂-adrenergic receptors in mouse liver alters the expression of gluconeogenic and glycolytic enzymes

Departments of ¹Immunology, ²Genetics, Development and Molecular Pathology, and ³Endocrinology, Institut Cochin, Institut National de la Santé et de la Recherche Médicale U 567/Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France

Submitted 9 March 2004 ; accepted in final form 24 November 2004

In the livers of humans and many other mammalian species, ₂-adrenergic receptors (₂-ARs) play an important role in the modulation of glucose production by glycogenolysis and gluconeogenesis. In male mice and rats, however, the expression and physiological role of hepatic ₂-ARs are rapidly lost with development under normal physiological conditions. We previously described a line of transgenic mice, F28 (André C, Erraji L, Gaston J, Grimber G, Briand P, and Guillet JG. Eur J Biochem 241: 417–424, 1996), which carry the human ₂-AR gene under the control of its own promoter. In these mice, hepatic ₂-AR levels are shown to increase rapidly after birth and, as in humans, be maintained at an elevated level in adulthood. F28 mice display strongly enhanced adenylyl cyclase responses to -AR agonists in their livers and, compared with normal mice, have increased basal hepatic adenylyl cyclase activity. In this report we demonstrate that, under normal physiological conditions, this increased ₂-AR activity affects the expression of the gluconeogenic and glycolytic key enzymes phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and L-pyruvate kinase and considerably decreases hepatic glycogen levels. Furthermore, we show that the effects of -adrenergic ligands on liver glycogen observed in humans are reproduced in these mice: liver glycogen levels are strongly decreased by the ₂-AR agonist clenbuterol and increased by the -AR antagonist propranolol. These transgenic mice open new perspectives for studying in vivo the hepatic ₂-AR system physiopathology and for testing the effects of -AR ligands on liver metabolism.

-adrenergic receptor; glycogen; glucose; phosphoenolpyruvate carboxykinase; L-pyruvate kinase