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-longs 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 functions of the enzyme adenylyl cyclase (AC). Stimulation of AC by guanine nucleotides in DM changed to the lesser extent, which argues in favor of preservation of functions of heterotrimeric Gs-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-agonists 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, whereas 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 animals with DM1 and DM2 and should be considered in the diagnostics and treatment of DM and its complications.
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Adamczak, M. and Wiecek, A., The adipose tissue as an endocrine organ, Semin. Nephrol., 2013, vol. 33, pp. 2–13.
Bremer, A.A. and Jialal, I., Adipose tissue dysfunction in nascent metabolic syndrome, J. Obes., 2013, vol. 2013, 393192, doi: 10.1155/2013/393192.
Muzzin, P., Revelli, J.P., Kuhne, F., Cocayne, J.D., McCombie, W.R., Venter, J.C., Giacobino, J.P., and Fraser, C.M., An adipose tissue-specific β-adrenergic receptor: molecular clonic and down-regulation in obesity, J. Biol. Chem., 1991, vol. 266, pp. 24053–24058.
Bégin-Heick, N., β-Adrenergic receptors and G-proteins in the ob/ob mouse, Int. J. Obes. Relat. Metab. Disord., 1996, vol. 20, pp. 32–35.
Collins, S., Daniel, K.W., Rohlifs, E.M., Ramkumar, V., Taylor, I.L., and Gettys, T.W., Impaired expression and functional activity of the β3- and β1-adrenergic receptors in adipose tissue of congenitally obese (c57bl/6j ob/ob) mice, Mol. Endocrinol., 1994, vol. 8, pp. 518–527.
Collins, S., Daniel, K.W., Petro, A.E., and Surwit, R.S., Strain-specific response to β3-adrenergic receptor agonist treatment of diet-induced obesity in mice, Endocrinol., 1997, vol. 138, pp. 405–413.
Gettys, T.W., Watson, P.M., Taylor, I.L., and Collins, S., Ru-486 (Mifepriston) ameliorates diabetes but does not correct deficient β-adrenergic signaling in adipocytes from mature c57bl /6j-ob/ob mice, Int. J. Obes. Relat. Metab. Disord., 1997, vol. 21, pp. 865–873.
Evans, B.A., Papaioannou, M., Anastasopoulos, F., and Summers, R.J., Differential regulation of β3-adrenoceptors in gut and adipose tissue in genetically obese (ob/ob) C57BL/6J-mice, Br. J. Pharmacol., 1998, vol. 124, pp. 763–771.
Dhalla, A.K., Santikul, M., Chisholm, J.W., Belardinelli, L., and Reaven, G.M., Comparison of the antilipolytic effects of an A1 adenosine receptor partial agonist in normal and diabetic rats, Diabetes Obes. Metab., 2009, vol. 11, pp. 95–101.
Strassheim, D., Milligan, G., and Houslay, M.D., Diabetes abolishes the GTP-dependent, but not the receptor-dependent inhibitory function of the inhibitory gyanine-nucleotide-binding regulatory protein (Gi) on adipocyte adenylate cyclase activity, Biochem. J., 1990, vol. 266, pp. 521–526.
Shpakov, A.O., Derkach, K.B., Chistyakova, O.V., Moyseyuk, I.V., and Bondareva, V.M., Effect of long diabetes caused by treatment with streptozotocin of the 1.5-month old rats on functional activity of adenylate cyclase system, Tsitologiya, 2013, vol. 55, no. 9, pp. 609–618.
Shpakov, A., Derkach, K., Moyseyuk, I., and Chistyakova, O.V., Alterations of hormone-sensitive adenylyl cyclase system in the tissues of rats with long-term streptozotocin diabetes and the influence of intranasal insulin, Dataset Papers Pharmacol., 2013, vol. 2013, 698435.
Derkach, K.B., Shpakov, A.O., Moyseyuk, I.V., and Chistyakova, O.V., Functional activity of adenylate cyclase system in brain, myocardium, and testes of rats with the 8- and 18-month neonatal diabetes, Dokl. RAN, 2013, vol. 448, no. 5, pp. 598–601.
Shpakov, A.O., Derkach, K.B., Moyseyuk, I.V., Chistyakova, O.V., and Bondareva, V.M., Hormonal sensitivity of adenylyl cyclase in the myocardium, brain, and testes of the 18-month-old non-diabetic and diabetic rats, Int. J. Biochem. Res. Rev., 2013, vol. 3, pp. 1–20.
Shpakov, A.O., Moyseyuk, I.V., Chistyakova, O.V., Derkach, K.B., Sukhov, I.B., and Bondareva, V.M., Treatment with intranasal insulin and serotonin restores sensitivity of adenylate cyclase to hormones in brain of rats with long-term neonatal diabetes, Byull. FCSKE im. V.A. Almazova, 2013, no. 1, pp. 21–27.
Shpakov, A.O., Kuznetsova, L.A., Plesneva, S.A., and Pertseva, M.N., Molecular mechanisms of change of sensitivity of adenylate cyclase signal system to biogenic amines in streptozotocin diabetes, Byull. Eksper. Biol. Med., 2005, vol. 140, no. 9, pp. 286–290.
Lewis, D.S., Cellucci, M.D., Masoro, E.J., and Yu, B.P., An improved method for the isolation of adipocyte plasma membranes, Anal. Biochem., 1979, vol. 96, pp. 236–245.
Shpakov, A.O., Shpakova, E.A., Tarasenko, I.I., Derkach, K.B., and Vlasov, G.P., The peptides mimicking the third intracellular loop of 5-hydroxytryptamine receptors of the types 1B and 6 selectively activate G proteins and receptor-specifically inhibit serotonin signaling via the adenylyl cyclase system, Int. J. Pept. Res. Ther., 2010, vol. 16, pp. 95–105.
Grujeras, A.B., Dias-Lagares, A., Carreira, M.C., Amil, M., and Casanueva, F.F., Oxidative stress associated to dysfunctional adipose tissue: a potentional link between obesity, type 2 diabetes mellitus and breast cancer, Free Radic. Res., 2013, vol. 47, pp. 243–256.
Murdolo, G., Piroddi, M., Luchetti, F., Tortoioli, C., Canonico, B., Zerbinati, C., Galli, F., and Luliano, L., Oxidative stress and lipid peroxidase by-products at the crossroad between adipose organ dysregulation and obesity-linked insulin resistance, Biochimie, 2013, vol. 95, pp. 585–594.
Shpakov, A.O. and Derkach, K.V., The functional state of hormone-sensitivity adenylyl cyclase signaling system in diabetes mellitus, J. Signal Transduct., 2013, vol. 2013, 594213, http://dx.doi.org/10.1155/2013.
Vendrell, J., El Bekay, R., Peral, B., Garcia Fuentes, E., Megia, A., Macias-Gonzales, M., Fernández Real, J., Jimenez-Gomez, Y., Escoté, X., Pachón, G., Simó, R., Selva, D.M., Malagón, M.M., and Tinahones, F.J., Study of the potential association of adipose tissue glp-1 receptor with obesity and insulin resistance, Endocrinol., 2011, vol. 152, pp. 4072–4079.
Shpakov, A.O., Functional state of regulated by biogenic amines and acetylcholine signal systems of brain in diabetes mellitus, Tsitologiya, 2012, vol. 54, no. 6, pp. 459–468.
Shpakov, A.O. and Derkach, K.V., Peptidergic brain signal systems in diabetes mellitus, Tsitologiya, 2012, vol. 54, no. 10, pp. 733–741.
Shpakov, A.O., Alterations in hormonal signaling systems in diabetes mellitus: origin, casuality and specificity, Endocrinol. Metab. Syndr., 2012, vol. 1, e106, doi: 10.4172/2161-1017.1000e1.
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Original Russian Text © K.V. Derkach, O.V. Chistyakova, A.O. Shpakov, 2014, published in Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 2014, Vol. 50, No. 2, pp. 85–91.
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Derkach, K.V., Chistyakova, O.V. & Shpakov, A.O. A change of hormonal regulation of adenylyl cyclase in epididymal adipose tissue of rats with experimental models of diabetes mellitus. J Evol Biochem Phys 50, 95–102 (2014). https://doi.org/10.1134/S002209301402001X
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DOI: https://doi.org/10.1134/S002209301402001X