Differential Regulation of Oxytocin Receptor in Various Adipose Tissue Depots and Skeletal Muscle Types in Obese Zucker Rats

Abstract

Multifunctional peptide oxytocin currently undergoes intensive research due to its proposed anti-obesity properties. Until now, little is known about regulation of oxytocin receptor in metabolically active tissues in obesity. The aim of the present study was to measure expression of oxytocin receptor upon obese phenotype with respect to the variety among adipose tissue and skeletal muscles with distinct anatomical localisation. Total homogenates were prepared from epididymal, retroperitoneal and inguinal adipose tissues as well as quadriceps and soleus muscle from lean and obese Zucker rats. Oxytocin receptor protein was determined by immunoblot. Interestingly, elevated oxytocin receptor was observed in epididymal adipose tissue of obese rats in contrast to its downregulation in subcutaneous and no change in retroperitoneal fat. In lean animals, oxytocin receptor protein was expressed at similar levels in all adipose depots. This uniformity was not observed in the case of skeletal muscle in which fibre type composition seems to be determinant of oxytocin receptor expression. Quadriceps muscle with the predominance of glycolytic fibres exhibits higher oxytocin receptor expression than almost exclusively oxidative soleus muscle. Oxytocin receptor protein levels were decreased in both skeletal muscles analysed upon obese phenotype. The present work demonstrates that even under identical endocrine circumstances, oxytocin receptor is differentially regulated in adipose tissue of obese rats depending on fat depot localisation. These results also imply which tissues may be preferentially targeted by oxytocin treatment in metabolic disease.

Key words

obesity - oxytocin - metabolic tissues

• References

• 1 Zhang H, Wu C, Chen Q, Chen X, Xu Z, Wu J, Cai D. Treatment of obesity and diabetes using oxytocin or analogs in patients and mouse models. PLoS One 2013; 8: e61477
• 2 Deblon N, Veyrat-Durebex C, Bourgoin L, Caillon A, Bussier AL, Petrosino S, Piscitelli F, Legros JJ, Geenen V, Foti M, Wahli W, Di Marzo V, Rohner-Jeanrenaud F. Mechanisms of the anti-obesity effects of oxytocin in diet-induced obese rats. PLoS One 2011; 6: e25565
• 3 Morton GJ, Thatcher BS, Reidelberger RD, Ogimoto K, Wolden-Hanson T, Baskin DG, Schwartz MW, Blevins JE. Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats. Am J Physiol Endocrinol Metab 2012; 302: E134-E144
• 4 Eckertova M, Ondrejcakova M, Krskova K, Zorad S, Jezova D. Subchronic treatment of rats with oxytocin results in improved adipocyte differentiation and increased gene expression of factors involved in adipogenesis. Br J Pharmacol 2011; 162: 452-463
• 5 Kimura T, Saji F, Nishimori K, Ogita K, Nakamura H, Koyama M, Murata Y. Molecular regulation of the oxytocin receptor in peripheral organs. J Mol Endocrinol 2003; 30: 109-115
• 6 Breton C, Haenggeli C, Barberis C, Heitz F, Bader CR, Bernheim L, Tribollet E. Presence of functional oxytocin receptors in cultured human myoblasts. J Clin Endocrinol Metab 2002; 87: 1415-1418
• 7 Bonne D, Cohen P. Characterization of oxytocin receptors on isolated rat fat cells. Eur J Biochem 1975; 56: 295-303
• 8 Gajdosechova L, Krskova K, Segarra AB, Spolcova A, Suski M, Olszanecki R, Zorad S. Hypooxytocinaemia in obese Zucker rats relates to oxytocin degradation in liver and adipose tissue. J Endocrinol 2014; 220: 333-343
• 9 Romero-Calvo I, Ocon B, Martinez-Moya P, Suarez MD, Zarzuelo A, Martinez-Augustin O, de Medina FS. Reversible Ponceau staining as a loading control alternative to actin in Western blots. Anal Biochem 2010; 401: 318-320
• 10 Welinder C, Ekblad L. Coomassie staining as loading control in Western blot analysis. J Proteome Res 2011; 10: 1416-1419
• 11 Sackmann-Sala L, Berryman DE, Munn RD, Lubbers ER, Kopchick JJ. Heterogeneity among white adipose tissue depots in male C57BL/6 J mice. Obesity (Silver Spring) 2012; 20: 101-111
• 12 DiGirolamo M, Fine JB, Tagra K, Rossmanith R. Qualitative regional differences in adipose tissue growth and cellularity in male Wistar rats fed ad libitum. Am J Physiol 1998; 274: R1460-R1467
• 13 Phillips MS, Liu Q, Hammond HA, Dugan V, Hey PJ, Caskey CJ, Hess JF. Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 1996; 13: 18-19
• 14 Perello M, Raingo J. Leptin activates oxytocin neurons of the hypothalamic paraventricular nucleus in both control and diet-induced obese rodents. PLoS One 2013; 8: e59625
• 15 Blevins JE, Schwartz MW, Baskin DG. Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size. Am J Physiol Regul Integr Comp Physiol 2004; 287: R87-R96
• 16 Cancello R, Tordjman J, Poitou C, Guilhem G, Bouillot JL, Hugol D, Coussieu C, Basdevant A, Bar Hen A, Bedossa P, Guerre-Millo M, Clement K. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 2006; 55: 1554-1561
• 17 Szeto A, Nation DA, Mendez AJ, Dominguez-Bendala J, Brooks LG, Schneiderman N, McCabe PM. Oxytocin attenuates NADPH-dependent superoxide activity and IL-6 secretion in macrophages and vascular cells. Am J Physiol Endocrinol Metab 2008; 295: E1495-E1501
• 18 Gealekman O, Guseva N, Hartigan C, Apotheker S, Gorgoglione M, Gurav K, Tran KV, Straubhaar J, Nicoloro S, Czech MP, Thompson M, Perugini RA, Corvera S. Depot-specific differences and insufficient subcutaneous adipose tissue angiogenesis in human obesity. Circulation 2011; 123: 186-194
• 19 Thibonnier M, Conarty DM, Preston JA, Plesnicher CL, Dweik RA, Erzurum SC. Human vascular endothelial cells express oxytocin receptors. Endocrinology 1999; 140: 1301-1309
• 20 Altirriba J, Poher AL, Caillon A, Arsenijevic D, Veyrat-Durebex C, Lyautey J, Dulloo A, Rohner-Jeanrenaud F. Divergent effects of oxytocin treatment of obese diabetic mice on adiposity and diabetes. Endocrinology 2014; 155: 4189-4201
• 21 Pette D, Staron RS. Cellular and molecular diversities of mammalian skeletal muscle fibers. Rev Physiol Biochem Pharmacol 1990; 116: 1-76
• 22 Lee ES, Uhm KO, Lee YM, Kwon J, Park SH, Soo KH. Oxytocin stimulates glucose uptake in skeletal muscle cells through the calcium-CaMKK-AMPK pathway. Regul Pept 2008; 151: 71-74
• 23 Elabd C, Cousin W, Upadhyayula P, Chen RY, Chooljian MS, Li J, Kung S, Jiang KP, Conboy IM. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat Commun 2014; 5: 4082
• 24 Stenholm S, Harris TB, Rantanen T, Visser M, Kritchevsky SB, Ferrucci L. Sarcopenic obesity: definition, cause and consequences. Curr Opin Clin Nutr Metab Care 2008; 11: 693-700
• 25 She P, Olson KC, Kadota Y, Inukai A, Shimomura Y, Hoppel CL, Adams SH, Kawamata Y, Matsumoto H, Sakai R, Lang CH, Lynch CJ. Leucine and protein metabolism in obese Zucker rats. PLoS One 2013; 8: e59443
• 26 Devost D, Girotti M, Carrier ME, Russo C, Zingg HH. Oxytocin induces dephosphorylation of eukaryotic elongation factor 2 in human myometrial cells. Endocrinology 2005; 146: 2265-2270