Possible involvement of glucocorticoids in 5α-dihydrotestosterone-induced PCOS-like metabolic disturbances in the rat visceral adipose tissue

Nikolić, Marina; Macut, Djuro; Djordjević, Ana; Veličković, Nataša; Nestorović, Nataša; Bursać, Biljana; Antić, Ivana Božić; Macut, Jelica Bjekić; Matić, Gordana; Milutinović, Danijela Vojnović

doi:10.1016/j.mce.2014.08.013

Cited by 29 publications

(13 citation statements)

References 47 publications

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“…The chosen dose of DHT was used to induce a hyperandrogenic state mimicking that is seen in women with PCOS (Fassnacht et al, 2003;Silfen et al, 2003). As we have shown (Nikolic et al, 2014) treatment of juvenile rats with DHT induces both reproductive and metabolic abnormalities similar to those seen in women with PCOS. Growing body of evidence supports a notion that women with PCOS display an increased prevalence of cardiovascular disease risk factors (Westerveld et al, 2008).…”

Section: Introduction ▼supporting

confidence: 56%

Cardiac Nitric Oxide Synthases and Na+/K+-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone

Tepavčević

Milutinović

Macut

et al. 2015

Exp Clin Endocrinol Diabetes

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Nitric oxide synthases (NOSs) and Na(+)/K(+)-ATPase are enzymes essential for regular functioning of the heart. Since both enzymes are under insulin and androgen regulation and since insulin action and androgen level were disturbed in polycystic ovary syndrome (PCOS), we hypothesized that cardiac nitric oxide (NO) production and sodium/potassium transport would be deteriorated in PCOS. To test our hypothesis we introduced animal model of PCOS based on dihydrotestosterone (DHT) treatment of female Wistar rats and analyzed protein expression, phosphorylation or subcellular localization of endothelial NOS (eNOS), inducible NOS (iNOS) and alpha subunits of Na(+)/K(+)-ATPase in the heart. Obtained results indicate that DHT treatment significantly decreased cardiac eNOS protein level and activating phosphorylation at serine 1,177, while inhibitory phosphorylation at threonine 495 was increased. In contrast to expression of eNOS, iNOS protein level in the heart of DHT-treated rats was significantly elevated. Furthermore, cardiac protein level of alpha 1 subunit of the ATPase, as well as its plasma membrane content, were decreased in rats with PCOS. In line with this, alpha 2 subunit protein level in fraction of plasma membranes was also significantly below control level. In conclusion, DHT treatment impaired effectiveness of NOSs and Na(+)/K(+)-ATPase in the female rat heart. Regarding the importance of NO production and sodium/potassium transport in the cardiac contraction and blood flow regulation, it implicates strong consequences of PCOS for heart functioning.

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Section: Introduction ▼supporting

confidence: 56%

Cardiac Nitric Oxide Synthases and Na+/K+-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone

Tepavčević

Milutinović

Macut

et al. 2015

Exp Clin Endocrinol Diabetes

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“…In this study we used animal model of PCOS obtained by the continuous subcutaneous administration of a nonaromatizable androgen DHT, which was previously shown to induce the main repro-ductive characteristics of PCOS similar to those seen in women with the syndrome [23]. Moreover, one of the most important characteristics of this animal model is the presence of PCOS-associated metabolic disturbances such as increased body mass, abdominal obesity and dyslipidemia.…”

Section: Discussionmentioning

confidence: 99%

“…The rats of the first group (Placebo group) were implanted with subcutaneous pellets lacking the bioactive component, while the rats from second group were implanted with subcutaneous pellets with continuousrelease of 5α-dihydrotestosterone (DHT group). The total dose of DHT was 7.5 mg with daily dose of 83 µg and was chosen as to induce a hyper-androgenic state mimicking that reported in women with PCOS [18][19][20][21][22][23]. The pellets were purchased from Innovative Research of America (Sarasota, Florida).…”

Section: Animals and Treatmentmentioning

confidence: 99%

“…All animals had ad libitum access to commercial chow and tap water. As we have previously described, the stage of cyclicity was determined by microscopic analysis of the predominant cell type in vaginal smears obtained daily from each animal from the 10th week to the end of the treatment [23]. All DHT-treated rats were acyclic, in diestrus phase of estrous cycle, while placebo rats had normal estrous cyclicity.…”

Section: Animals and Treatmentmentioning

confidence: 99%

“…Frozen adipose tissue was homogenized (w/v = 1:1) in icecold homogenization buffer (20 mM Tris-HCl, pH 7.2, 10 % glycerol, 50 mM NaCl, 1 mM EDTA-Na 2 , 1 mM EGTA-Na 2 , 2 mM DTT, protease and phosphatase inhibitors). The homogenates were further processed to obtain cytoplasmatic, nuclear and membrane fractions, as described previously [23]. All steps were conducted at 4 °C and the obtained fractions were stored at − 70 °C.…”

Section: Preparation Of Cytoplasmic Nuclear and Membrane Fractions Omentioning

confidence: 99%

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

Milutinović

Nikolić

Veličković

et al. 2017

Exp Clin Endocrinol Diabetes

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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.

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Environmental Impact on the Hypothalamus-Pituitary-Ovary Axis

et al. 2022

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Possible involvement of glucocorticoids in 5α-dihydrotestosterone-induced PCOS-like metabolic disturbances in the rat visceral adipose tissue

Cited by 29 publications

References 47 publications

Cardiac Nitric Oxide Synthases and Na+/K+-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone

Cardiac Nitric Oxide Synthases and Na+/K+-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone

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

Environmental Impact on the Hypothalamus-Pituitary-Ovary Axis

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