5α-DIHYDROTESTOSTERONE TREATMENT INDUCES METABOLIC CHANGES ASSOCIATED WITH POLYCYSTIC OVARY SYNDROME WITHOUT INTERFERING WITH HYPOTHALAMIC LEPTIN AND GLUCOCORTICOID SIGNALING

Authors

  • Marina Nikolić Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, 142 Despot Stefan Blvd., 11000 Belgrade
  • Nataša Veličković Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, 142 Despot Stefan Blvd., 11000 Belgrade
  • Ana Djordjevic Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, 142 Despot Stefan Blvd., 11000 Belgrade
  • Biljana Bursać Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, 142 Despot Stefan Blvd., 11000 Belgrade
  • Djuro Macut Institute of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia and School of Medicine, University of Belgrade, Dr Subotića 13, 11000 Belgrade
  • Ivana Božić Antić Institute of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia and School of Medicine, University of Belgrade, Dr Subotića 13, 11000 Belgrade
  • Jelica Bjekić Macut CHC Bežanijska kosa, Bežanijska kosa bb, 11080 Belgrade
  • Gordana Matić Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, 142 Despot Stefan Blvd., 11000 Belgrade
  • Danijela Vojnović Milutinović Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, 142 Despot Stefan Blvd., 11000 Belgrade

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. It is a heterogenous disorder, with hyperandrogenism, chronic anovulation and polycystic ovaries as basic characteristics, and associated metabolic syndrome features. Increased secretion of leptin and leptin resistance are common consequences of obesity. Leptin is a hormone with anorexigenic effects in the hypothalamus. Its function in the regulation of energy intake and consumption is antagonized by glucocorticoids. By modulating leptin signaling and inflammatory processes in the hypothalamus, glucocorticoids can contribute to the development of metabolic disturbances associated with central energy disbalance. The aim of the study was to examine the relationship between hypothalamic leptin, glucocorticoid and inflammatory signaling in the development of metabolic disturbances associated with PCOS. The study was conducted on an animal model of PCOS generated by a continual, 90-day treatment of female rats with 5α-dihydrotestosterone (DHT). The model exhibited all key reproductive and metabolic features of the syndrome. mRNA and/or protein levels of the key components of hypothalamic glucocorticoid, leptin and inflammatory pathways, presumably contributing to energy disbalance in DHT-treated female rats, were measured. The results indicated that DHT treatment led to the development of hyperphagia and hyperleptinemia as metabolic features associated with PCOS. However, these metabolic disturbances could not be ascribed to changes in hypothalamic leptin, glucocorticoid or inflammatory signaling pathways in DHT-treated rats.

 

Keywords: DHT; hypothalamus; leptin; glucocorticoids; inflammation

 

Received: December 14, 2015; Revised: December 23, 2015; Accepted: December 28, 2015; Published online: January 14, 2016

Downloads

Download data is not yet available.

References

Rotterdam Eshre Asrm-Sponsored Pcos Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19-25.

Conway G, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Franks S, Gambineri A, Kelestimur F, Macut D, Micic D, Pasquali R, Pfeifer M, Pignatelli D, Pugeat M, Yildiz BO. The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol. 2014;171(4):P1-29.

Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013;6:1-13.

Diamanti-Kandarakis E, Papavassiliou AG, Kandarakis SA, Chrousos GP. Pathophysiology and types of dyslipidemia in PCOS. Trends Endocrinol Metab. 2007;18(7):280-5.

Kanaya N, Vonderfecht S, Chen S. Androgen (dihydrotestosterone)-mediated regulation of food intake and obesity in female mice. J Steroid Biochem Mol Biol. 2013;138:100-6.

Barber TM, Franks S. Adipocyte biology in polycystic ovary syndrome. Mol Cell Endocrinol. 2013;373(1-2):68-76.

Rodriguez-Cuenca S, Monjo M, Proenza AM, Roca P. Depot differences in steroid receptor expression in adipose tissue: possible role of the local steroid milieu. Am J Physiol Endocrinol Metab. 2005;288(1):E200-7.

Diamanti-Kandarakis E. Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev Mol Med. 2008;10:e3.

Tchernof A, Despres JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93(1):359-404.

Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Aspects Med. 2013;34(1):1-11.

Ahima RS, Osei SY. Molecular regulation of eating behavior: new insights and prospects for therapeutic strategies. Trends Mol Med. 2001;7(5):205-13.

Ribiere C, Plut C. Nutritional regulation of leptin signaling. Curr Hypertens Rep. 2005;7(1):11-6.

Pan H, Guo J, Su Z. Advances in understanding the interrelations between leptin resistance and obesity. Physiol Behav. 2014;130:157-69.

Myers MG, Cowley MA, Munzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008;70:537-56.

Rojas J, Chavez M, Olivar L, Rojas M, Morillo J, Mejias J, Calvo M, Bermudez V. Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth. Int J Reprod Med. 2014;2014:719050.

Morris DL, Rui L. Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab. 2009;297(6):E1247-59.

Yang R, Barouch LA. Leptin signaling and obesity: cardiovascular consequences. Circ Res. 2007;101(6):545-59.

Munzberg H, Bjornholm M, Bates SH, Myers MG, Jr. Leptin receptor action and mechanisms of leptin resistance. Cell Mol Life Sci. 2005;62(6):642-52.

Wauman J, Tavernier J. Leptin receptor signaling: pathways to leptin resistance. Front Biosci (Landmark Ed). 2011;16:2771-93.

La Fleur SE. The effects of glucocorticoids on feeding behavior in rats. Physiol Behav. 2006;89(1):110-4.

Gathercole LL, Stewart PM. Targeting the pre-receptor metabolism of cortisol as a novel therapy in obesity and diabetes. J Steroid Biochem Mol Biol. 2010;122(1-3):21-7.

Wang M. The role of glucocorticoid action in the pathophysiology of the Metabolic Syndrome. Nutr Metab (Lond). 2005;2(1):3.

Czegle I, Csala M, Mandl J, Benedetti A, Karadi I, Banhegyi G. G6PT-H6PDH-11β-HSD1 triad in the liver and its implication in the pathomechanism of the metabolic syndrome. World J Hepatol. 2012;4(4):129-38.

Mlinar B, Marc J, Jensterle M, Bokal EV, Jerin A, Pfeifer M. Expression of 11β-hydroxysteroid dehydrogenase type 1 in visceral and subcutaneous adipose tissues of patients with polycystic ovary syndrome is associated with adiposity. J Steroid Biochem Mol Biol. 2011;123(3-5):127-32.

Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013;132(5):1033-44.

Staab CA, Maser E. 11β-hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation. J Steroid Biochem Mol Biol. 2010;119(1-2):56-72.

Nikolić M, Macut D, Djordjevic A, Veličković N, Nestorović N, Bursać B, Antić IB, Macut JB, Matić G, Vojnović Milutinović D. Possible involvement of glucocorticoids in 5α-dihydrotestosterone-induced PCOS-like metabolic disturbances in the rat visceral adipose tissue. Mol Cell Endocrinol. 2015;399:22-31.

Fassnacht M, Schlenz N, Schneider SB, Wudy SA, Allolio B, Arlt W. Beyond adrenal and ovarian androgen generation: Increased peripheral 5α-reductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(6):2760-6.

Silfen ME, Denburg MR, Manibo AM, Lobo RA, Jaffe R, Ferin M, Levine LS, Oberfield SE. Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents. J Clin Endocrinol Metab. 2003;88(10):4682-8.

Duncombe WG. The Colorimetric Micro-Determination of Non-Esterified Fatty Acids in Plasma. Clin Chim Acta. 1964;9:122-5.

Spector T. Refinement of the coomassie blue method of protein quantitation. A simple and linear spectrophotometric assay for less than or equal to 0.5 to 50 microgram of protein. Anal Biochem. 1978;86(1):142-6.

Patel R, Williams-Dautovich J, Cummins CL. Minireview: new molecular mediators of glucocorticoid receptor activity in metabolic tissues. Mol Endocrinol. 2014;28(7):999-1011.

Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006;443(7109):289-95.

Geer EB, Islam J, Buettner C. Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue function and lipid metabolism. Endocrinol Metab Clin North Am. 2014;43(1):75-102.

Downloads

Published

2016-09-02

How to Cite

1.
Nikolić M, Veličković N, Djordjevic A, Bursać B, Macut D, Božić Antić I, Bjekić Macut J, Matić G, Vojnović Milutinović D. 5α-DIHYDROTESTOSTERONE TREATMENT INDUCES METABOLIC CHANGES ASSOCIATED WITH POLYCYSTIC OVARY SYNDROME WITHOUT INTERFERING WITH HYPOTHALAMIC LEPTIN AND GLUCOCORTICOID SIGNALING. Arch Biol Sci [Internet]. 2016Sep.2 [cited 2024Dec.3];68(3):473-81. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/962

Issue

Section

Articles

Most read articles by the same author(s)