Overexpression of beta2-adrenergic receptors in mouse liver alters the expression of gluconeogenic and glycolytic enzymes.
In the livers of humans and many other mammalian species, beta2-adrenergic receptors (beta2-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 beta2-ARs are rapidly lost with development under normal physiological conditions. We previously described a line of transgenic mice, F28 (Andre C, Erraji L, Gaston J, Grimber G, Briand P, and Guillet JG. Eur J Biochem 241: 417-424, 1996), which carry the human beta2-AR gene under the control of its own promoter. In these mice, hepatic beta2-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 beta-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 beta2-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 beta-adrenergic ligands on liver glycogen observed in humans are reproduced in these mice: liver glycogen levels are strongly decreased by the beta2-AR agonist clenbuterol and increased by the beta-AR antagonist propranolol. These transgenic mice open new perspectives for studying in vivo the hepatic beta2-AR system physiopathology and for testing the effects of beta-AR ligands on liver metabolism.
Erraji-Benchekroun
Loubna
L
Department of Immunology, Institut Cochin, Institut National de la Santé et de la Recherche Médicale, Paris, France.
Couton
Dominique
D
Postic
Catherine
C
Borde
Isabelle
I
Gaston
Jesintha
J
Guillet
Jean-Gérard
JG
André
Claudine
C
D000262:Adenylyl Cyclases / Q000096:biosynthesis*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D015152:Blotting, Northern; D002976:Clenbuterol / Q000494:pharmacology; D004435:Eating / Q000502:physiology; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000096:biosynthesis / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D011770:Pyruvate Kinase / Q000096:biosynthesis / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D006003:Glycogen; D011433:Propranolol; D011770:Pyruvate Kinase; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D000262:Adenylyl Cyclases; D002976:Clenbuterol