A change of hormonal regulation of adenylyl cyclase in epididymal adipose tissue of rats with experimental models of diabetes mellitus

Abstract

One of the key causes of diabetes mellitus (DM) and its complications are hormonal disturbances in functioning of hormonal signaling systems, including the adenylyl cyclase signaling system (ACSS). The goal of this work was to study the functional state and hormonal sensitivity of ACSS in the epididymal adipose tissue of male rats in the 7-month model of mild type 1 DM (DM1), in the 18-month neonatal model of type 2 DM (DM2), and in the taken for comparison model of the 30-day acute DM1. It is shown for the first time that in adipocytes from the epididymal fat of rats with the studied DM models the basal AC activity and its stimulation by forskolin were decreased, which indicates a weakening of the catalytic function of the enzyme adenylyl cyclase (AC). Stimulation of AC by guanine nucleotides in DM changed to the lesser extent, which speaks in favor of preservation of functions of heterotrimeric G(s)-proteins in the epididymal fat. In rats with DM1 the sensitivity of AC of adipocytes to agonists of β-adrenergic receptors (β-AR), activators of lipolysis, remained practically unchanged, while in animals with DM2 the AC stimulating effects of β-AR-agonists were reduced or completely blocked, like in the case of β3-AR-agonist BRL-37344 and CL-316243. In adipocytes of rats with DM1 the AC inhibitory effect of N6-cyclopentyladenosine, agonist of type 1 adenosine receptors (Aden1R), an inhibitor of lipolysis, was attenuated, whe- reas in DM2 this effect was completely preserved. Thus, in the epididymal adipose tissue of rats with DM1 the antilipolytic AC cascades including Aden1R were decreased and the stimulation of AC by β-AR-agonists was preserved, whereas in rats with DM2 the β-AR-mediated AC cascades activating lipolysis were reduced, but Aden1R-mediated AC cascades inhibiting lipolysis did not change. The changes of hormonal regulation of ACSS in adipocytes from the epididymal fat lead to disturbances of the metabolic status of animal with DM1 and DM2 and should be considered in the diagnostics and treatment of DM and its complications.