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Background: Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with increased obesity, hyperandrogenism, and altered brown adipose tissue (BAT) thermogenesis. MicroRNAs play critical functions in brown adipocyte differentiation and maintenance. We aim to study the role of microRNA-21 (miR-21) in altered energy homeostasis and BAT thermogenesis in a PCOS mouse model of peripubertal androgen exposure. Methods: Three-week-old miR-21 knockout (miR21KO) or wild-type (WT) female mice were treated with dihydrotestosterone (DHT) or vehicle for 90 days. Body composition was determined by EchoMRI. Energy expenditure (EE), oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER) were measured by indirect calorimetry. Androgen receptor (AR), and markers of adipogenesis, de novo lipogenesis, angiogenesis, extracellular matrix remodeling, and thermogenesis were quantified by RT-qPCR and/or Western-blot. Results: MiR-21 ablation attenuated DHT-mediated increase in body weight while having no effect on fat or BAT mass. MiR-21 ablation attenuated DHT-mediated BAT AR upregulation. MiR-21 ablation did not alter EE; however, miR21KO DHT-treated mice have reduced VO2, VCO2, and RER. MiR-21 ablation reversed DHT-mediated decrease in food intake and increase in sleep time. MiR-21 ablation decreased some adipogenesis (Adipoq, Pparγ, and Cebpβ) and extracellular matrix remodeling (Mmp-9 and Timp-1) markers expression in DHT-treated mice. MiR-21 ablation abolished DHT-mediated increases in thermogenesis markers Cpt1a and Cpt1b, while decreasing CIDE-A expression. Conclusions: Our findings suggest that BAT miR-21 may play a role in regulating DHT-mediated thermogenic dysfunction in PCOS. Modulation of BAT miR-21 levels could be a novel therapeutic approach for the treatment of PCOS-associated metabolic derangements. Highlights: MicroRNA-21 genetic ablation decreased excess androgen-mediated increase in body weight and lean mass. Excess androgens decreased oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER), without affecting energy expenditure (EE) in microRNA-21 knockout mice. MicroRNA-21 genetic ablation decreased the expression of some brown adipose tissue markers of adipogenesis in excess androgen-treated mice. MicroRNA-21 genetic ablation decreased the expression of some brown adipose tissue markers of extracellular matrix remodeling in excess androgen-treated mice. MicroRNA-21 genetic ablation reversed the androgen-mediated increased expression of some genes related to thermogenesis in brown adipose tissue of androgen-treated mice. Plain language summary: Polycystic ovary syndrome (PCOS) is a common hormone disorder in premenopausal women, often linked to obesity and abnormal brown fat tissue activity. Women with PCOS have elevated male hormones, which are responsible for many metabolic problems. Our study focuses on understanding the role of microRNA-21 (miR-21) in the energy balance and brown fat tissue activity in a PCOS mouse model. We studied female mice with and without miR-21, treating them with a male hormone. We measured body composition and energy expenditure. We also analyzed the levels of specific genes and proteins related to fat tissue and energy production. Our findings showed that mice lacking miR-21 had less weight gain in response to male hormones, without fat or brown fat tissue mass changes. They also had reduced energy production, changed eating habits, and altered expression of genes related to fat tissue and energy production. In conclusion, our study suggests that miR-21 in brown fat tissue may regulate the energy imbalance caused by male hormones in PCOS. Adjusting miR-21 levels in brown fat tissue could be a new way to address the metabolic issues associated with PCOS. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP)-induced Acute Liver Failure (ALF) is recognized as the most common cause of ALF in Western societies. APAP-induced ALF is characterized by coagulopathy, hepatic encephalopathy, multi-organ failure, and death. MicroRNAs are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. MicroRNA-21 (miR-21) is dynamically expressed in the liver and is involved in the pathophysiology of both acute and chronic liver injury models. We hypothesize that miR-21genetic ablation attenuates hepatotoxicity following acetaminophen intoxication. Eight-week old miR-21knockout (miR21KO) or wild-type (WT) C57BL/6N male mice were injected with acetaminophen (APAP, 300 mg/kg BW) or saline. Mice were sacrificed 6 or 24 h post-injection. MiR21KO mice presented attenuation of liver enzymes ALT, AST, LDH compared with WT mice 24 h post-APAP treatment. Moreover, miR21KO mice had decreased hepatic DNA fragmentation and necrosis than WT mice after 24 h of APAP treatment. APAP-treated miR21KO mice showed increased levels of cell cycle regulators CYCLIN D1 and PCNA, increased autophagy markers expression (Map1LC3a, Sqstm1) and protein (LC3AB II/I, p62), and an attenuation of the APAP-induced hypofibrinolytic state via (PAI-1) compared with WT mice 24 post-APAP treatment. MiR-21 inhibition could be a novel therapeutic approach to mitigate APAP-induced hepatotoxicity and enhance survival during the regenerative phase, particularly to alter regeneration, autophagy, and fibrinolysis. Specifically, miR-21 inhibition could be particularly useful when APAP intoxication is detected at its late stages and the only available therapy is minimally effective. [ABSTRACT FROM AUTHOR]

Abstract Research question To examine associations between sperm mitochondrial DNA copy number (mtDNAcn), sperm mitochondrial DNA deletions (mtDNAdel), semen parameters and clinical infertility in an IVF setting. Design A total of 125 sperm samples were collected from men undergoing assisted reproductive procedures in an IVF clinic in Western Massachusetts, USA. Sperm mtDNAcn and mtDNAdel were measured by probe-based quantitative polymerase chain reaction. Semen parameters, clinical diagnoses of infertility, and infertility based on consecutive semen parameters, were fitted with mtDNAcn and mtDNAdel in linear models. The utility of sperm mtDNAcn and mtDNAdel to predict infertility was assessed by receiver operating characteristic curves. Results Adjusting for relevant covariates, both sperm mtDNAcn and mtDNAdel were associated with lower sperm concentration, count, motility and morphology (P ≤ 0.03). Sperm mtDNAcn and mtDNAdel were also associated with increased risks of clinical infertility based on current and consecutive semen samples. Sperm mtDNAcn had high predictive accuracy for consecutive diagnoses of clinical infertility (C-statistic: 0.91), whereas sperm mtDNAdel had moderate predictive accuracy (C-statistic: 0.75). Conclusions Sperm mtDNAcn is a measure of consecutive abnormal semen parameters and has promise as a diagnostic test. [ABSTRACT FROM AUTHOR]

Background Phthalates, a chemical class of plasticizers, are ubiquitous environmental contaminants that have been associated with oxidative stress. Mitochondria DNA copy number (mtDNAcn) and DNA deletions (mtDNAdel) are emerging biomarkers for cellular oxidative stress and environment exposures. Objectives To examine associations of urinary phthalate metabolite and isoprostane concentrations on sperm mtDNAcn and mtDNAdel in male partners undergoing assisted reproductive technologies (ART). Methods Ninety-nine sperm samples were collected from male partners undergoing ART at Baystate Medical Center in Springfield, MA as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). Seventeen urinary phthalate metabolite concentrations were analyzed by the Centers for Disease Control using tandem mass spectrometry. Urinary 15-F2t-isoprostane concentrations, a biomarker of lipid peroxidation, were measured using a competitive enzyme-linked immunosorbent assay. A triplex qPCR method was used to determine the relative quantification of mtDNAcn and mtDNAdel. Results Sperm mtDNAcn and mtDNAdel were positively correlated (Spearman rho = 0.31; p = .002). Adjusting for age, BMI, current smoking, race, and measurement batch, urinary monocarboxy-isononyl phthalate (MCNP) concentrations were positively associated with mtDNAcn (β = 1.63, 95% CI: 0.14, 3.11). Other urinary phthalate metabolite and isoprostane concentrations were not associated with sperm mtDNAcn or mtDNAdel. Conclusions Among this cohort of male ART participants, those with higher MCNP had higher mtDNAcn; other phthalate metabolites and isoprostane were not associated with mtDNAcn and mtDNAdel. Given our relatively small sample size, our results should be interpreted with caution. Future research is needed to replicate the findings in larger studies and among sperm samples obtained from the general population. [ABSTRACT FROM AUTHOR]

R4063 --> 860.1 --> Introduction: Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive‐age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and insulin resistance, both being risk factors associated with cardiovascular disease. Micro‐RNAs are small, non‐coding RNAs capable of altering gene expression by binding to specific mRNA targets. MicroRNA‐21(miR21) is cell‐specifically expressed and dynamically regulated in tissues that are implicated in cardiometabolic dysfunction in PCOS including the liver, skeletal muscle, and the heart. We hypothesize that miR‐21 genetic ablation exacerbates androgen‐induced dysregulation of insulin signaling to modify insulin resistance and cardiac damage in a mouse model of PCOS. Methods: Three‐week‐old peripubertal miR‐21 knockout (miR21KO) or wild‐type (WT) C57BL/6N female mice were treated s.c. with dihydrotestosterone (DHT, 8 mg) or vehicle for 90 days. Fasting glucose was determined by an enzymatic method and both fasting insulin and advanced glycation end products (AGES) were measured by ELISA. microRNA, mRNA, and protein levels were quantified by RT‐qPCR and Western‐blot. Data were analyzed by t‐test or two‐way ANOVA. All differences are considered significant p<0.05. Results: In WT animals DHT treatment increased miR21 expression in the soleus muscle (2.15±0.47‐fold, p<0.05), with a trend to increase in the tibialis anterior muscle (1.25‐fold), and the liver (1.41‐fold) compared with their vehicle counterparts. DHT‐treated miR21KO females showed exacerbated insulin resistance, having increased HOMA‐IR compared with both vehicle miR21KO and WT groups (6.50 ± 3.64 vs. 3.32±1.83 and 3.16±1.31, p<0.05) calculated using fasting insulin and glucose. In the soleus, miR21KO DHT‐treated mice showed an increase in Irs2 (1.45‐fold, p<0.05) compared with vehicle WT, whereas no increase was found in DHT‐treated WT animals. DHT‐treated miR21KO animals showed significantly increased Akt2 (1.40‐fold) and the glucose transporter Slc2a2 (1.24‐fold) mRNA expression in the liver. Additionally, liver protein expression of total mTOR was increased only in miR21KO DHT‐treated animals (2.40, p<0.05) compared to vehicle WT animals. Lastly, miR21KO increased left ventricular advanced glycation end products (AGEs), having significantly higher AGEs compared to all three treatment groups (3.10±0.52μg /mg protein, p<0.05). Conclusions: Our results suggest that miR21 upregulation in insulin sensitive tissues is a compensatory mechanism to counteract androgen‐inducted dysregulation of insulin signaling pathways and downstream cardiac damage. The differences observed in androgen‐treated mice highlight the potential importance of miR21 in the crosstalk between several insulin signaling networks. Notably, given the worsened DHT‐induced insulin resistance and increased left ventricular AGEs in miR21KO animals, a miR‐21 mimic may be a potential novel therapeutic option for women with PCOS. [ABSTRACT FROM AUTHOR]

The susceptibility and the severity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with hyperandrogenism, obesity, and preexisting pulmonary, metabolic, renal, and cardiac conditions. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with obesity, hyperandrogenism, and cardiometabolic dysregulations. We analyzed cardiac, renal, circulatory, and urinary SARS-CoV-2 viral entry proteins (ACE2, TMPRSS2, TMPRSS4, furin, cathepsin L, and ADAM17) and androgen receptor (AR) expression, in a peripubertal androgen exposure model of PCOS. Peripubertal female mice were treated with dihydrotestosterone (DHT) and low (LFD) or high (HFD) fat diet for 90 days. HFD exacerbated DHT-induced increase in body weight, fat mass, and cardiac and renal hypertrophy. In the heart, DHT upregulated AR protein in both LFD and HFD, ACE2 in HFD, and ADAM17 in LFD. In the kidney, AR protein expression was upregulated by both DHT and HFD. Moreover, ACE2 and ADAM17 were upregulated by DHT in both diets. Renal TMPRSS2, furin, and cathepsin L were upregulated by DHT and differentially modulated by the diet. DHT upregulated urinary ACE2 in both diets, while neither treatment modified serum ACE2. Renal AR mRNA expression positively correlated with Ace2, Tmprss2, furin, cathepsin L, and ADAM17. Our findings suggest that women with PCOS could be a population with a high risk of COVID-19-associated cardiac and renal complications. Furthermore, our study suggests that weight loss by lifestyle modifications (i.e., diet) could potentially mitigate COVID-19-associated deleterious cardiorenal outcomes in women with PCOS. [ABSTRACT FROM AUTHOR]

SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19. [ABSTRACT FROM AUTHOR]

Abstract Dravet syndrome is a severe, early-onset epileptic encephalopathy frequently resulting from de novo mutations of SCN1A. Mice with heterozygous deletion of Scn1a (Scn1a +/−) model many features of Dravet syndrome, including spontaneous seizures and premature lethality. Scn1a +/− mice exhibit variable phenotype penetrance and expressivity dependent upon the strain background. On the 129S6/SvEvTac (129) strain, Scn1a +/− mice do not display an overt phenotype. However Scn1a +/− mice on the [129S6xB6]F1 strain (F1. Scn1a +/−) exhibit juvenile-onset spontaneous seizures and premature lethality. QTL mapping identified several modifier loci responsible for strain-dependent differences in survival of Scn1a +/− mice, but these loci do not account for all the observed phenotypic variance. Global RNA-seq analysis was performed to identify additional genes and pathways that may contribute to variable phenotypes. Hippocampal gene expression was analyzed in wild-type (WT) and Scn1a +/− mice on both F1 and 129 strains, at two time points during disease development. There were few gene expression differences between 129.WT and 129. Scn1a +/− mice and approximately 100 genes with small expression differences (6–36%) between F1.WT and F1. Scn1a +/− mice. Strain-specific gene expression differences were more pronounced, with dozens of genes with >1.5-fold expression differences between 129 and F1 strains. Age-specific and seizure-related gene expression differences were most prominent, with hundreds of genes with >2-fold differences in expression identified between groups with and without seizures, suggesting potential differences in developmental trajectory and/or homeostatic plasticity during disease onset. Global expression differences in the context of Scn1a deletion may account for strain-dependent variation in seizure susceptibility and survival observed in Scn1a +/− mice. Highlights • Gene expression was surveyed at pre- and peri-onset ages in Scnla+/− mice on epilepsy permissive and resistant strains. • A limited number of gene expression differences were seen between Scn1a+/− and wild-type mice in the absence of seizures. • Strain-dependent differences were shared among all ages and genotypes in expression of genes enriched for ribosomal proteins. • Age-dependent differences were shared among strains and genotypes in expression of nervous system development genes. • Unique differences in signaling/plasticity genes were observed in Scn1a+/− mice with seizures versus those without seizures. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS), characterized by androgen excess and ovulatory dysfunction, is associated with a high prevalence of obesity and insulin resistance (IR) in women. We demonstrated that sodium–glucose cotransporter-2 inhibitor (SGLT2i) administration decreases fat mass without affecting IR in the PCOS model. In male models of IR, administration of SGLT2i decreases oxidative stress and improves mitochondrial function in white adipose tissue (WAT). Therefore, we hypothesized that SGLT2i reduces adiposity via improvement in mitochondrial function and oxidative stress in WAT in PCOS model. Methods: Four-week-old female rats were treated with dihydrotestosterone for 90 days (PCOS model), and SGLT2i (empagliflozin) was co-administered during the last 3 weeks. Body composition was measured before and after SGLT2i treatment by EchoMRI. Subcutaneous (SAT) and visceral (VAT) WAT were collected for histological and molecular studies at the end of the study. Results: PCOS model had an increase in food intake, body weight, body mass index, and fat mass/lean mass ratio compared to the control group. SGLT2i lowered fat mass/lean ratio in PCOS. Glucosuria was observed in both groups, but had a larger magnitude in controls. The net glucose balance was similar in both SGLT2i-treated groups. The PCOS SAT had a higher frequency of small adipocytes and a lower frequency of large adipocytes. In SAT of controls, SGLT2i increased frequencies of small and medium adipocytes while decreasing the frequency of large adipocytes, and this effect was blunted in PCOS. In VAT, PCOS had a lower frequency of small adipocytes while SGLT2i increased the frequency of small adipocytes in PCOS. PCOS model had decreased mitochondrial content in SAT and VAT without impacting oxidative stress in WAT or the circulation. SGLT2i did not modify mitochondrial function or oxidative stress in WAT in both treated groups. Conclusions: Hyperandrogenemia in PCOS causes expansion of WAT, which is associated with decreases in mitochondrial content and function in SAT and VAT. SGLT2i increases the frequency of small adipocytes in VAT only without affecting mitochondrial dysfunction, oxidative stress, or IR in the PCOS model. SGLT2i decreases adiposity independently of adipose mitochondrial and oxidative stress mechanisms in the PCOS model. Highlights: Androgen excess in PCOS model is associated with decreased markers of mitochondrial content in both subcutaneous and visceral white adipose tissue. Androgen excess in PCOS model is associated with increased frequency of small adipocytes in subcutaneous white adipose tissue while decreasing frequency of small adipocytes in visceral white adipose tissue. SGLT2 inhibition did not modify markers of mitochondrial content or oxidative stress in either subcutaneous or visceral white adipose tissue in PCOS model. SGLT2 inhibition increased frequency of small adipocytes in both subcutaneous and visceral white adipose tissue in control rats; however, SGLT2 inhibition only increased frequency of small adipocytes in visceral white adipose tissue in PCOS model. [ABSTRACT FROM AUTHOR]

R3899 --> 745.5 --> Background: Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive age women. PCOS is characterized by hyperandrogenemia, oligo‐ or anovulation and polycystic ovaries and is associated with obesity and white adipose tissue (WAT) dysregulation. The deleterious metabolic profile of women with PCOS is exacerbated by obesity. However, the molecular mechanisms that mediate WAT dysfunction in PCOS, as well as its modulation by the diet, are poorly understood. We aim to investigate the effect of an obesogenic diet on androgen‐mediated WAT hypertrophy by assessing the adipocyte size of the different WAT depots [mesenteric fat (MF), subcutaneous fat (SCF) and retroperitoneal fat (RPF)] using a well‐established model of PCOS in mice. Methods: Three‐week old female mice (C57BL/6J) were implanted with Silastic tubes filled with the androgen dihydrotestosterone (DHT, 8.0 mg, S.C.) or vehicle (empty tubes). Animals were fed high‐fat diet (HFD; 60% kcal fat) or low‐fat diet (LFD; 10% kcal fat, sucrose‐matched) for 90 days. Weekly body weights and body composition (EchoMRI) were assessed. Animals were sacrificed and multiple WAT depots (MF, SCF and RPF) were harvested for histological analysis. Formalin‐fixed paraffin‐embedded tissues from the three WAT depots were sectioned (5 µm thick) and stained with hematoxylin and eosin. The stained sections were imaged at 40X magnification. Adipocyte size (cross‐sectional area) was determined using ImageJ software with the Adiposoft plugin [~2,000 adipocytes/section, 3 sections/animal, n = 6/group]. GraphPad Prism 8.4.2 was used for statistical analysis, and P‐values of 0.05 were considered statistically significant. Results: LFD‐fed DHT‐treated mice showed significant increases in body weight (28.00 ± 0.60 vs. 23.59 ± 0.41 g, p<0.05), lean mass (21.70 ± 0.30 vs. 20.04 ± 0.23 g, p<0.05), and fat mass (6.20 ± 0.50 vs. 3.42 ± 0.33 g, p<0.05) compared to their vehicle‐treated controls. Adipocyte size analysis showed that LFD‐fed DHT‐ treated mice have significantly larger adipocytes when assessed in MF (1512.0 ± 15.55 vs. 833.3 ± 6.50 µm2, p<0.05), SCF (1907.0 ± 22.04 vs. 1395.0 ± 12.43 µm2, p<0.05) and RPF (2284.0 ± 26.20 vs. 1396.0 ± 11.61 µm2, p<0.05), compared to their vehicle‐treated controls. Notably, HFD‐fed DHT‐treated mice showed greater MF and RPF adipocyte size compared to HFD‐fed vehicle‐treated mice, which was not observed in SCF. Interestingly, HFD exacerbated DHT‐mediated increases in body weight (1.54‐fold), lean mass (1.17‐fold), and fat mass (3.03‐fold) compared to LFD‐fed DHT‐treated mice. Additionally, the increase in adipocyte size in all fat depots in response to DHT was greater in mice fed HFD by 1.50‐fold compared to those fed LFD. Conclusion and significance: The hypertrophic effect of androgens on the WAT is modulated by the diet. Increased adipocyte size is associated with insulin resistance in women with PCOS. Our results may help explain why obesity is associated with a worsened metabolic profile in women with PCOS at the cellular level. Weight loss with a low‐fat diet may be an effective approach to ameliorate WAT dysfunction and the subsequent metabolic dysregulation in PCOS. [ABSTRACT FROM AUTHOR]

R3481 --> 856.2 --> Background: Polycystic ovary syndrome (PCOS), the most common endocrine disorder in reproductive‐age women, is characterized by oligo‐ or anovulation, hyperandrogenism, and polycystic ovaries. Both animal models and women with PCOS exhibit inflammation, obesity, and renal damage. The molecular mechanisms that mediate renal injury and dysfunction in PCOS, as well as its modulation by the diet are poorly understood. The JAK/STAT3 pathway, which is activated by interleukin‐6 (IL‐6) and leptin receptors, is involved in the pathophysiology of different models of renal injury. Despite its chronic activation in extra‐renal tissues in PCOS and obesity models, the role of the JAK/STAT3 pathway in PCOS‐mediated renal damage remains unknown. We aim to test the hypothesis that an obesogenic diet, via increased leptin and IL‐6, activates the JAK/STAT3 signaling pathway to exacerbate androgen‐induced renal injury. Methods: Three‐week‐old peripubertal female mice were implanted with Silastic tubes filled with the non‐aromatizable androgen dihydrotestosterone (DHT, 8 mg) or vehicle (empty tubes). Animals were fed either a high‐fat diet (HFD; 60% kcal fat) or a low‐fat diet (LFD; 10% kcal fat, sucrose‐matched) for 90 days. Fat mass (EchoMRI), serum leptin (ELISA), kidney weight (gravimetry), and urinary albumin to creatinine ratio (UACR, clinical chemistry analyzer) were measured. Markers of renal inflammation [IL‐6, tumor necrosis factor‐α (TNF‐α)], oxidative stress [NADPH oxidase2 (Nox2)], and fibrosis [collagen I, collagen III, transforming growth factor‐β (TGF‐β), and fibronectin] were quantified by RT‐qPCR. Western blot analysis of active STAT3 [phosphorylated‐STAT3 (Tyr705)] and total STAT3 proteins expression in the kidneys was also performed. Results: In LFD‐fed mice, DHT increased fat mass (20.28 ± 1.10 vs. 6.78 ± 0.43 g, p<0.05), serum leptin (1114.13 ± 133.68 vs. 299.27± 25.32 pg/mL, p<0.05), kidney weight (33.79 ± 1.35 vs. 26.52 ± 1.08 g, p<0.05) and UACR (1,227 ± 420 vs. 404 ± 169 μg albumin/g creatinine, p<0.05). DHT also increased the expression of renal inflammatory markers (TNF‐α and IL‐6). Notably, while DHT upregulated the expression of the fibrotic marker TGF‐β in LFD‐fed mice, it only induced the expression of Collagen I and Nox2 in the HFD‐fed mice. Furthermore, HFD exacerbated DHT‐mediated increases in adiposity and circulating leptin and IL‐6, as well as renal inflammation, hypertrophy, and UACR. The disturbance in the aforementioned parameters was associated with increased renal STAT3 phosphorylation in HFD‐fed DHT‐treated mice compared to LFD‐ or HFD‐fed controls (2.00‐ and 2.86‐fold, respectively, p<0.05). Conclusion and significance: Our findings suggest that diet‐induced obesity plays a significant role in the renal outcomes in PCOS, and that increased STAT3 activation may explain the exacerbated renal injury in HFD‐fed DHT‐treated female mice. JAK/STAT3 pathway modulation could be novel therapeutic approach for diet‐induced renal injury in PCOS. The implications of inhibiting specific STAT3 pathway components on the exacerbated renal impairment caused by obesity in our model of PCOS are currently being investigated. [ABSTRACT FROM AUTHOR]