The functional activity of the adenylate cyclase system in the brains of rats with metabolic syndrome induced by immunization with peptide 11-25 of the type 4 melanocortin receptor

摘要

The melanocortin system of the brain, which includes melanocortin receptors of the fourth type (M4R), plays a key role in the regulation of energy homeostasis and controls functions of the nervous system. Inhibition of M4R results in obesity and the metabolic syndrome, which presumably occur due to changes in the neuromediator systems of the brain. To examine this hypothesis, we examined the effect of long-term immunization of rats with the BSA-conjugated K-[TSLHLWNRSSHGLHG(11-25)]-A peptide (K-[11-25]-A), which corresponds to the extracellular N-terminal domain of M4R, on the activity of the hormone-sensitive adenylate cyclase signaling system (ACSS) of the brain. In rats that were immunized numerous times with the BSA conjugate (the I group), we observed an increase in body weight, impaired glucose tolerance, insulin resistance, and dyslipidemia. At 13 months after the beginning of the experiment, we evaluated the ACSS activity in synaptosomal membranes from the brain. The basal activity of AC and its regulation by GppNHp and forskolin did not differ from the control. In the I group both the AC-stimulating effects of the alpha-melanocyte-stimulating hormone (alpha-MSH), M4R-agonist THIQ, dopamine, and pituitary AC-activating polypeptide and the AC-inhibiting effects of serotonin and 5-nonyloxytryptamine, an agonist of 5-hydroxytryptamine receptor (5-HTR) of the 1B/1D-subtype, decreased. The affinity of M4R to agonists did not change. The AC-stimulating effect of the M3R agonist gamma-MSH was enhanced, which is a compensation for the weakening of M4R functions. The AC-stimulating effects of serotonin, EMD-386088, an agonist of 6 type 5-HTR relaxin, and noradrenaline, as well as the inhibitory effects of noradrenaline, the D-2-agonist bromocriptine, and somatostatin in the I group did not change. Thus, inhibition of M4R as a result of immunization with the BSA conjugate of the K-[11-25]-A peptide alters the sensitivity of the ACSS of the rat brain to peptides of melanocortin family and other neurohormones. These alterations are characterized by hormonal and receptor specificity and may be one of the causes of insulin resistance, metabolic syndrome, and functional disturbances in the CNS and at the periphery under conditions of M4R deficit.