Overexpression of β₂-adrenergic receptors in mouse liver alters the expression of gluconeogenic and glycolytic enzymes

Abstract

.-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...

Alterations of epinephrine-induced gluconeogenesis in aging

“…Epinephrine secreted from the adrenal medulla prepares the body to meet an emergency. Circulating glucagon and epinephrine activate cellular signals that catalyze components of adenylate cyclase via the stimulatory guanine nucleotide binding regulatory protein Gαs (Jelinek et al, 1993, Erraji-Benchekroun et al, 2005. This signal increases formation of cAMP and other transcription factors.…”

β1-Adrenergic Receptor Signaling Activates the Epithelial Calcium Channel, Transient Receptor Potential Vanilloid Type 5 (TRPV5), via the Protein Kinase A Pathway

“…1b, neg ctrl panel) and staining of liver tissue (Fig. 1b, liver panel) reported to be negative for both ␤1-AR and ␤2-AR (27,28). mRNA expression of ␤1-AR (Adrb1) and ␤2-AR (Adrb2) in DCT2/CNT cells isolated from pTRPV5-EGFP mice using the COPAS Biosorter, was determined by real-time PCR.…”

The Characteristics of Hepatic Gsα-cAMP Axis in HSHF Diet-Fed Obese Insulin Resistance Rats and Genetic Diabetic Mice

“…27) Loubna et al also found increased ADRB 2 expression in the liver of F28 mice could protect liver cells from apoptosis and lower the body mass index, mainly due to the ADRB 2 linked increase of hepatic cAMP activity. 28) Unexpectedly, there were some differences of hepatic Gsα-cAMP signal axis in high IR stage in HSHF-diet rats. The hepatic Gsα-cAMP signal axis was desensitized and almost reduced to that of normal chow-diet rats, in the face of chronic HSHF-diet stimulation.…”