Altered expression of hepatic beta-adrenergic receptors in aging rats: implications for age-related metabolic dysfunction in liver

Increased beta-adrenergic receptor (beta-AR)-mediated activation of adenylyl cyclase (AC) in rat liver during aging has been linked to age-related increases in hepatic glucose output and hepatosteatosis. In this study. we investigated the expression of beta-ARs, individual receptor subtypes, and G protein-coupled receptor (GPCR) regulatory proteins in livers from aging rats. Radioligand-binding studies demonstrated that beta-AR density increased by greater than threefold in hepatocyte membranes from senescent (24-mo-old) compared with young adult (7-mo-old) rats and that this phenomenon was blocked by food restriction, which is known to retard aging processes in rodents. Competition-binding studies revealed a mixed population of beta(1)- and beta(2)-AR subtypes in liver membranes over the adult life span. with a trend for greater beta(2)-AR density with age. Expression of both beta-AR subtype mRNAs in rat liver increased with age, whereas beta(2)- but not beta(1)-AR protein levels declined in livers of old animals. Immunoreactive beta(2)- but not beta(1)-ARs were preferentially distributed in pericentral hepatic regions. Levels of GRK2/3 and beta-arrestin 2 proteins, which are involved in downregulation of agonist-activated GPCRs, including beta-ARs, increased during aging. Insofar as sympathetic tone increases with age, our findings suggest that, despite enhanced agonist-mediated downregulation of hepatic beta-ARs preferentially affecting the beta(2)-AR subtype. increased generation of both receptor subtypes during aging augments the pool of plasma membrane-bound beta-ARs coupled to AC in hepatocytes. This study thus identifies one or both beta-AR subtypes as possible therapeutic targets involved in aberrant hepatic processes of glucose and lipid metabolism during aging.