Exp Clin Endocrinol Diabetes 2017; 125(08): 522-529
DOI: 10.1055/s-0043-104531
Article
© Georg Thieme Verlag KG Stuttgart · New York

Enhanced Inflammation without Impairment of Insulin Signaling in the Visceral Adipose Tissue of 5α-Dihydrotestosterone-Induced Animal Model of Polycystic Ovary Syndrome

Danijela Vojnović Milutinović
1   Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
,
Marina Nikolić
1   Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
,
Nataša Veličković
1   Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
,
Ana Djordjevic
1   Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
,
Biljana Bursać
1   Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
,
Jelena Nestorov
1   Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
,
Ana Teofilović
1   Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
,
Ivana Božić Antić
2   Clinic of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia and Faculty of Medicine, University of Belgrade, Belgrade, Serbia
,
Jelica Bjekić Macut
3   UMC Bežanijska kosa, Bežanijska kosa bb, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
,
Abdulbaset Shirif Zidane
1   Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
,
Gordana Matić
1   Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia
,
Djuro Macut
2   Clinic of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia and Faculty of Medicine, University of Belgrade, Belgrade, Serbia
› Author Affiliations
Further Information

Publication History

received 15 June 2016
revised 26 January 2017

accepted 22 February 2017

Publication Date:
13 April 2017 (online)

Abstract

Polycystic ovary syndrome is a heterogeneous endocrine and metabolic disorder associated with abdominal obesity, dyslipidemia and insulin resistance. Since abdominal obesity is characterized by low-grade inflammation, the aim of the study was to investigate whether visceral adipose tissue inflammation linked to abdominal obesity and dyslipidemia could lead to impaired insulin sensitivity in the animal model of polycystic ovary syndrome.

Female Wistar rats were treated with nonaromatizable 5α-dihydrotestosterone pellets in order to induce reproductive and metabolic characteristics of polycystic ovary syndrome. Glucose, triglycerides, non-esterified fatty acids and insulin were determined in blood plasma. Visceral adipose tissue inflammation was evaluated by the nuclear factor kappa B intracellular distribution, macrophage migration inhibitory factor protein level, as well as TNFα, IL6 and IL1β mRNA levels. Insulin sensitivity was assessed by intraperitoneal glucose tolerance test and homeostasis model assessment index, and through analysis of insulin signaling pathway in the visceral adipose tissue.

Dihydrotestosterone treatment led to increased body weight, abdominal obesity and elevated triglycerides and non-esterified fatty acids, which were accompanied by the activation of nuclear factor kappa B and increase in macrophage migration inhibitory factor, IL6 and IL1β levels in the visceral adipose tissue. In parallel, insulin sensitivity was affected in 5α-dihydrotestosterone-treated animals only at the systemic and not at the level of visceral adipose tissue.

The results showed that abdominal obesity and dyslipidemia in the animal model of polycystic ovary syndrome were accompanied with low-grade inflammation in the visceral adipose tissue. However, these metabolic disturbances did not result in decreased tissue insulin sensitivity.

 
  • References

  • 1 Legro RS, Arslanian SA, Ehrmann DA. et al. Diagnosis and treatment of polycystic ovary syndrome: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013; 98: 4565-4592
  • 2 Conway G, Dewailly D, Diamanti-Kandarakis E. et al. European survey of diagnosis and management of the polycystic ovary syndrome: Results of the ESE PCOS special interest group’s questionnaire. Eur J Endocrinol 2014; 171: 489-498
  • 3 Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: An update on mechanisms and implications. Endocr Rev 2012; 33: 981-1030
  • 4 Svendsen PF, Nilas L, Norgaard K. et al. Obesity, body composition and metabolic disturbances in polycystic ovary syndrome. Hum Reprod 2008; 23: 2113-2121
  • 5 Jung UJ, Choi MS. Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014; 15: 6184-6223
  • 6 Weisberg SP, McCann D, Desai M. et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808
  • 7 Piya MK, McTernan PG, Kumar S. Adipokine inflammation and insulin resistance: the role of glucose, lipids and endotoxin. J Endocrinol 2013; 216: T1-T15
  • 8 Xu A, Chan KW, Hoo RL. et al. Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes. J Biol Chem 2005; 280: 18073-18080
  • 9 Gonzalez F. Inflammation in Polycystic Ovary Syndrome: Underpinning of insulin resistance and ovarian dysfunction. Steroids 2012; 77: 300-305
  • 10 Baker RG, Hayden MS, Ghosh S. NF-kappaB, inflammation, and metabolic disease. Cell Metab 2011; 13: 11-22
  • 11 Sanchez-Zamora YI, Rodriguez-Sosa M. The role of MIF in type 1 and type 2 diabetes mellitus. J Diabetes Res 2014; 2014: 804519
  • 12 Lue H, Kleemann R, Calandra T. et al. Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microbes Infect 2002; 4: 449-460
  • 13 Azziz R, Carmina E, Dewailly D. et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: The complete task force report. Fertil Steril 2009; 91: 456-488
  • 14 Ovalle F, Azziz R. Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus. Fertil Steril 2002; 77: 1095-1105
  • 15 Macut D, Simic T, Lissounov A. et al. Insulin resistance in non-obese women with polycystic ovary syndrome: Relation to byproducts of oxidative stress. Exp Clin Endocrinol Diabetes 2011; 119: 451-455
  • 16 Panidis D, Tziomalos K, Misichronis G. et al. Insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study. Hum Reprod 2012; 27: 541-549
  • 17 Pirola L, Johnston AM, Van Obberghen E. Modulation of insulin action. Diabetologia 2004; 47: 170-184
  • 18 Fassnacht M, Schlenz N, Schneider SB. et al. Beyond adrenal and ovarian androgen generation: Increased peripheral 5 alpha-reductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88: 2760-2766
  • 19 Silfen ME, Denburg MR, Manibo AM. et al. Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): Comparison between nonobese and obese adolescents. J Clin Endocrinol Metab 2003; 88: 4682-4688
  • 20 Manneras L, Cajander S, Holmang A. et al. A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology 2007; 148: 3781-3791
  • 21 Yanes LL, Romero DG, Moulana M. et al. Cardiovascular-renal and metabolic characterization of a rat model of polycystic ovary syndrome. Gend Med 2011; 8: 103-115
  • 22 Sara L, Antal P, Masszi G. et al. Arteriolar insulin resistance in a rat model of polycystic ovary syndrome. Fertil Steril 2012; 97: 462-468
  • 23 Nikolić M, Macut D, Djordjevic A. et al. Possible involvement of glucocorticoids in 5alpha-dihydrotestosterone-induced PCOS-like metabolic disturbances in the rat visceral adipose tissue. Mol Cell Endocrinol 2015; 399: 22-31
  • 24 Duncombe WG. The Colorimetric Micro-Determination of Non-Esterified Fatty Acids in Plasma. Clin Chim Acta 1964; 9: 122-125
  • 25 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: 142-146
  • 26 Veličković N, Djordjevic A, Vasiljević A. et al. Tissue-specific regulation of inflammation by macrophage migration inhibitory factor and glucocorticoids in fructose-fed Wistar rats. Br J Nutr 2013; 110: 456-465
  • 27 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408
  • 28 Macut D, Panidis D, Glisic B. et al. Lipid and lipoprotein profile in women with polycystic ovary syndrome. Can J Physiol Pharmacol 2008; 86: 199-204
  • 29 Kelly CC, Lyall H, Petrie JR. et al. Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2001; 86: 2453-2455
  • 30 Escobar-Morreale HF, Villuendas G, Botella-Carretero JI. et al. Obesity, and not insulin resistance, is the major determinant of serum inflammatory cardiovascular risk markers in pre-menopausal women. Diabetologia 2003; 46: 625-633
  • 31 Knebel B, Janssen OE, Hahn S. et al. Increased low grade inflammatory serum markers in patients with Polycystic ovary syndrome (PCOS) and their relationship to PPARgamma gene variants. Exp Clin Endocrinol Diabetes 2008; 116: 481-486
  • 32 Mohlig M, Spranger J, Osterhoff M. et al. The polycystic ovary syndrome per se is not associated with increased chronic inflammation. Eur J Endocrinol 2004; 150: 525-532
  • 33 Auron PE. The interleukin 1 receptor: Ligand interactions and signal transduction. Cytokine Growth Factor Rev 1998; 9: 221-237
  • 34 O’Neill LA, Greene C. Signal transduction pathways activated by the IL-1 receptor family: Ancient signaling machinery in mammals, insects, and plants. J Leukoc Biol 1998; 63: 650-657
  • 35 Yan S, Xu Z, Lou F. et al. NF-kappaB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis. Nat Commun 2015; 6: 7652
  • 36 Dali-Youcef N, Mecili M, Ricci R. et al. Metabolic inflammation: Connecting obesity and insulin resistance. Ann Med 2013; 45: 242-253
  • 37 Suganami T, Tanimoto-Koyama K, Nishida J. et al. Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol 2007; 27: 84-91
  • 38 Finucane OM, Reynolds CM, McGillicuddy FC. et al. Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance. Proc Nutr Soc 2012; 71: 622-633
  • 39 Verschuren L, Kooistra T, Bernhagen J. et al. MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease. Circ Res 2009; 105: 99-107
  • 40 Luque-Ramirez M, Escobar-Morreale HF. Polycystic ovary syndrome as a paradigm for prehypertension, prediabetes, and preobesity. Curr Hypertens Rep 2014; 16: 500
  • 41 Randeva HS, Tan BK, Weickert MO. et al. Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev 2012; 33: 812-841
  • 42 Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116: 1793-1801
  • 43 Jager J, Gremeaux T, Cormont M. et al. Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 2007; 148: 241-251
  • 44 Vozarova B, Weyer C, Hanson K. et al. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res 2001; 9: 414-417
  • 45 Tepavčević S, Vojnović Milutinović D, Macut D. et al. Dihydrotestosterone deteriorates cardiac insulin signaling and glucose transport in the rat model of polycystic ovary syndrome. J Steroid Biochem Mol Biol 2014; 141: 71-76
  • 46 Khodabandehloo H, Gorgani-Firuzjaee S, Panahi G. et al. Molecular and cellular mechanisms linking inflammation to insulin resistance and beta-cell dysfunction. Transl Res 2016; 167: 228-256