PCOS

A parallel line of research linking glucocorticoid signalling to the molecular bases of polycystic ovary sindrome (PCOS), a basically reproductive disease very often characterized and pathophysiologically linked with prominent MS characteristics (IR, dyslipidemia, obesity), was conducted in an adequate rat animal model, and the study’s interesting novel findings were well received in the relevant scientific and medical circuits. Firstly, we delivered 5α-dihydrotestosterone (5α-DHT) and placebo pellets subcutaneously to prepubertal female Wistar rats immediately post weaning, and then did a morphological and biochemical characterization of this PCOS model 90 days after, thereby confirming that our treatment led to the development of the most important reproductive and metabolic characteristics of PCOS: anoestrus, increased number of athretic ovarian follicules, anovulation, decreased system insulin sensitivity, dyslipidemia and obesity ^{[1], [2]}. Then we succeeded in being first to mechanistically link glucocorticoids with adipocyte hypertrophy and visceral obesity in a rat model of PCOS ^[1]. Namely, we studied the changes in the VAT prereceptor metabolism of glucocorticoids and measured its increase, reflected in the changes of transcription and protein levels of 11β-HSD1 and local glucocorticoid concentrations. We also detected VAT nuclear GR accumulation, in concert with an increased expression of the GR-regulated prolipogenic genes (lipin-1, SREBP-1, fatty acid synthase (FAS)) and the results of histological analyses which showed adipocyte hypertrophy. Additionally, glucocorticoids showed no influence on the local lipolytic processes, as indicated by the unchanged hormone sensitive lipase (HSL) and adipocyte triglyceride lipase (ATGL) levels in VAT of our PCOS model ^[1]. Further analyses indicated that although levels of proinflammatory cytokines are significantly increased, they could not be associated with VAT insulin resistance as evidenced by the unchanged levels of the inhibited phospho form of IRS-1 (pIRS1-Ser³⁰⁷) although it was clearly shown at the systemic level^[3]. DHT-treated animals also showed signs of hyperphagia, and hyperleptinemia, but we were not able to link these symptoms with glucocorticoid-regulated neuroendocrine control of food consumption nor the related inflammatory processes in the hypothalamus of our PCOS model¹⁷ (the levels of ObRb iRNA and proteins, NPY and SOCS3, all remained unchanged, as did the 11β-HSD1, H6PDH, GR, NFκB proteins and TNF-α and IL-6 iRNA levels).

[1] Nikolić M, Macut D, Djordjevic A, Veličković N, Nestorović N, Bursać B, Božić Antić I, Bjekić-Macut J, Matić G, Vojnović Milutinović D. (2015) Possible involvement of glucocorticoids in 5α-DHT-induced PCOS-like metabolic disturbances in the rat visceral adipose tissue. Molecular and Cellular Endocrinology 399: 22-31.

[2] Nikolić M, Veličković N, Djordjevic A, Bursac B, Macut Dj, Božić-Antić I, Bjekić Macut J, Matić G, Vojnović Milutinović D. (2016) 5α-dihydrotestosterone treatment induces metabolic changes associated with polycystic ovary syndrome without interfering with hypothalamic leptin and glucocorticoid signaling. Archives of Biological Sciences, doi: 10.2298/ABS151214001N

[3] Milutinović DV, Nikolić M, Veličković N, Djordjevic A, Bursać B, Nestorov J, Teofilović A, Božić IB, Macut JB, Zidane AS, Matić G, Macut D. (2017) Enhanced Inflammation without Impairment of Insulin Signaling in the Visceral Adipose Tissue of 5α-Dihydrotestosterone-Induced Animal Model of Polycystic Ovary Syndrome. Exp Clin Endocrinol Diabetes 125: 522-529.