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, which carry the human ₂-AR gene under the control of its own promoter. In these mice, hepatic ₂-AR levels are shown to rapidly increase 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 to 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 (PEPCK), glucose-6-phosphatase (G6Pase) and L-pyruvate kinase (L-PK), 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.