Interaction of Glucocorticoids with Glucagon and Epinephrine in the Control of Gluconeogenesis and Glycogenolysis in Liver and of Lipolysis in Adipose Tissue

The effects of glucagon and epinephrine on gluconeogenesis and glycogenolysis in liver and of catecholamines and adrenocorticotrophic hormone on lipolysis in adipose tissue were examined in normal and adrenalectomized rats. Glucagon or epinephrine stimulation of glucose synthesis from lactate was markedly reduced in isolated perfused livers from fasted, adrenal-deficient rats. Administration in vivo of the glucocorticoid dexamethasone 30 min prior to perfusion restored the gluconeogenic response to glucagon. Cortisol and dexamethasone were also effective when added to the perfusion medium, but had no effect in the absence of glucagon. Cyclic AMP (adenosine 3′,5′-monophosphate) accumulation was normal or increased in livers from adrenalectomized rats perfused without hormones or with glucagon or epinephrine. Gluconeogenesis in livers from fasted, adrenal-deficient rats was relatively unresponsive to cyclic AMP or dibutyryl cyclic AMP added to the perfusion medium. Hypophysectomized rats also showed an impairment of cyclic AMP activation of gluconeogenesis which was corrected by treatment with cortisol but not growth hormone. High concentrations of epinephrine, glucagon, and cyclic AMP stimulated glucose production and lactate gluconeogenesis in livers from fed, adrenalectomized rats. However, more nearly physiological concentrations of the hormones did not activate glucose release and phosphorylase normally in such livers. Livers from fed, adrenalectomized rats also showed diminished activation of gluconeogenesis and phosphorylase by exogenous cyclic AMP. Omission of Ca++ from the perfusion medium did not alter control or cyclic AMP-stimulated glycogenolysis or gluconeogenesis in normal rats. Addition of ethyleneglycol-bis (β-aminoethyl ether)-N,N′-tetraacetic acid to Ca++-free medium reduced the control rates of glycogenolysis and gluconeogenesis but did not abolish the stimulation by cyclic AMP. Lowering the Ca++ level did not accentuate the impairment of cyclic AMP-stimulated glycogenolysis in fed, adrenalectomized rats nor did increasing the Ca++ level relieve the impairment of cyclic AMP-stimulated gluconeogenesis. It is therefore concluded that variations in plasma Ca++ are not important in the regulation of hepatic glycogenolysis or gluconeogenesis. Epinephrine stimulation of free fatty acid and glycerol release is impaired in epididymal fat pads or isolated fat cells from adrenalectomized rats. Cyclic AMP accumulation in response to epinephrine is, however, increased in fat pads from such animals. Activation of lipolysis by norepinephrine, adrenocorticotrophic hormone, or cyclic AMP is also reduced in fat cells from adrenal-deficient rats. These studies indicate that adrenal glucocorticoids are required for normal activation of gluconeogenesis, glycogenolysis, and lipolysis by epinephrine and other hormones. Part of the function of the steroids appears to be to maintain normal sensitivity of these processes to cyclic AMP. The possibility is discussed that the corticoids exert their permissive effects by preserving a normal intracellular ionic environment.