.-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][418][419][420][421][422][423][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 THE INTERACTION OF CIRCULATING CATECHOLAMINES with adrenergic receptors plays an important role in the regulation of lipid, protein, and carbohydrate metabolism. Epinephrine enhances lipolysis in adipose tissue, glycogenolysis in muscle, and glucose production in liver that result from both direct stimulation of glycogenolysis and indirect stimulation of gluconeogenesis (3,21,26).Both ␣ 1 -and ␤ 2 -adrenergic receptors (␣ 1 -ARs and ␤ 2 -ARs) are expressed in the liver and are involved in the direct effect of catecholamines. Whereas ␣ 1 -ARs are linked to the phosphoinositide turnover/calcium mobilization, ␤ 2 -ARs mediate their effects via the adenylyl cyclase/cAMP-signaling pathway. The relative contribution of the two adrenergic receptor subtypes to catecholamine-induced glycogenolysis depends on animal species, sex, and physiological state (16,19).In the livers of most species, including humans, the number of both ␣ 1 -and ␤ 2 -ARs is high, and catecholamine-stimulated glycogenolysis occurs primarily via ␤ 2 -ARs in normal physiological conditions (3,17,21,26,28,34). In male rats and mice, however, there is a reversal in predominance from ␤ 2 -ARs to ␣ 1 -ARs during development. The ␤ 2 -AR density, ␤ 2 -AR-induced cAMP responses, and ␤ 2 -AR-dependent glycogen...

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