Polycystic ovary syndrome (PCOS) is the most common ovulatory defect in women. Although most PCOS patients are obese, a subset of PCOS women are lean but show similar risks for adverse fertility outcomes. A lean PCOS mouse model was created using prenatal androgen administration. This developmentally programmed mouse model was used for this study. Our objective was to investigate if mitochondrial structure and functions were compromised in oocytes obtained from lean PCOS mouse. The lean PCOS mouse model was validated by performing glucose tolerance test, HbA1c levels, body weight and estrous cycle analyses. Oocytes were isolated and were used to investigate inner mitochondrial membrane potential, oxidative stress, lipid peroxidation, ATP production, mtDNA copy number, transcript abundance and electron microscopy. Our results demonstrate that lean PCOS mice have similar weight to that of the controls but exhibit glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of their oocytes show impaired inner mitochondrial membrane function, elevated reactive oxygen species (ROS) and increased RNA transcript abundance. Electron microscopy of the oocytes showed impaired mitochondrial ultrastructure. In conclusion, the lean PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial ultrastructure and function.
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Neil R Chappell, Beth Zhou, Amy K Schutt, William E Gibbons and Chellakkan S Blesson
Solène Castellnou, Alexandre Vasiljevic, Véronique Lapras, Véronique Raverot, Eudeline Alix, Françoise Borson-Chazot, Emmanuel Jouanneau, Gérald Raverot and Hélène Lasolle
Somatostatin receptor type 5 (SST5) is inconsistently expressed by corticotroph tumors, with higher expression found in corticotropinomas having ubiquitin-specific protease 8 (USP8) mutations. Aims were to study the correlation between characteristics of corticotropinomas and SST5 expression/USP8 mutation status and to describe the response to pasireotide in five patients.
Retrospective cohort study.
Clinico-biochemical, radiological and pathological data of 62 patients, operated for a functioning or silent corticotropinoma between 2013 and 2017, were collected. SST5 expression was measured by immunohistochemistry (clone UMB-4, Abcam, IRS > 1 being considered positive), and Sanger sequencing was performed on 50 tumors to screen for USP8 mutations.
SST5 expression was positive in 26/62 pituitary tumors. A moderate or strong IRS was found in 15/58 corticotropinomas and in 13/35 functioning corticotropinomas. Among functioning tumors, those expressing SST5 were more frequent in women (22/24 vs 9/15, P = 0.04) and had a lower grade (P = 0.04) compared to others. USP8 mutations were identified in 13/50 pituitary tumors and were more frequent in functioning compared to silent tumors (11/30 vs 2/20, P = 0.05). SST5 expression was more frequent in USP8mut vs USP8wt tumors (10/11 vs 7/19, P = 0.007). Among treated patients, normal urinary free cortisol levels were obtained in three patients (IRS 0, 2 and 6), while a four-fold decrease was observed in one patient (IRS 4).
SST5 expression appears to be associated with functioning, USP8mut and lower grade corticotropinomas. A correlation between SST5 expression or USP8mut and response to pasireotide remains to be confirmed.
Li Li, Qifa Song and Xi Yang
Insufficient insulin release plays a crucial role in the development of unhealthy status in patients with obesity; the present study aimed to classify these patients by the indices for insulin resistance and insulin release. After the indices from OGTT were assessed to achieve high differentiability and low redundancy in classifying patients, HOMA-IR and IGI30min were chosen to classify the patients using K-means clustering method. A total of 249 non-diabetic patients with obesity were classified into four groups. In Group 1, 19 patients were characteristic of high insulin resistance and high insulin release, as well as well-controlled glucose levels, the highest BMI, the youngest age, and the highest early phase release of insulin. In Group 2, 38 patients were unhealthiest in terms of high insulin resistance, reduced insulin release and IGT status. Group 3 consisted of 63 patients that were healthiest with low insulin resistance and high insulin release. In Group 4, 46 IGT patients and 14 IFG patients were identified among 129 patients that showed low insulin resistance, low insulin release, moderate obesity and older age. These concurrent impotent insulin release, older age, and moderate obesity indicated decreasing obesity with increasing age and reduced insulin release. The classification of patients with obesity using K-means clustering method by HOMA-IR and IGI30min provides more information about the development of obesity and unhealthy status. The patients with distinct insulin resistance and insulin release should be followed up, especially for those with reduced or even absent insulin response to glucose stimulation.
Monika Karczewska-Kupczewska, Agnieszka Nikołajuk, Radosław Majewski, Remigiusz Filarski, Magdalena Stefanowicz, Natalia Matulewicz and Marek Strączkowski
Insulin resistance is a major pathophysiological link between obesity and its metabolic complications. Weight loss (WL) is an effective tool to prevent obesity-related diseases; however, the mechanisms of an improvement in insulin sensitivity (IS) after weight-reducing interventions are not completely understood. The aim of the present study was to analyze the relationships between IS and adipose tissue (AT) expression of the genes involved in the regulation of lipolysis in obese subjects after WL.
Fifty-two obese subjects underwent weight-reducing dietary intervention program. The control group comprised 20 normal-weight subjects, examined at baseline only. Hyperinsulinemic-euglycemic clamp and s.c. AT biopsy with subsequent gene expression analysis were performed before and after the program.
AT expression of genes encoding lipases (PNPLA2, LIPE and MGLL) and lipid-droplet proteins enhancing (ABHD5) and inhibiting lipolysis (PLIN1 and CIDEA) were decreased in obese individuals in comparison with normal-weight individuals. The group of 38 obese participants completed dietary intervention program and clamp studies, which resulted in a significant WL and an improvement in mean IS. However, in nine subjects from this group IS did not improve in response to WL. AT expression of PNPLA2, LIPE and PLIN1 increased only in the group without IS improvement.
Excessive lipolysis may prevent an improvement in IS during WL. The change in AT PNPLA2 and LIPE expression was a negative predictor of the change in IS after WL.
Sebastião Freitas de Medeiros, Márcia Marly Winck Yamamoto, Matheus Antônio Souto de Medeiros, Bruna Barcelo Barbosa, José Maria Soares Junior and Edmund Chada Baracat
To verify whether aging can modify the clinical and biochemical characteristics of women with polycystic ovary syndrome (PCOS).
Material and methods
This observational cross-sectional study was conducted at the reproductive endocrinology clinics of Julio Muller University Hospital and Tropical Institute of Reproductive Medicine in Cuiabá, MT, Brazil, between 2003 and 2017. Both, 796 PCOS and 444 non-PCOS normal cycling women underwent the same examination. PCOS was diagnosed using the Rotterdam criteria as recommended for adolescent and adult subjects. Anthropometric, metabolic, and endocrinological modifications with aging were initially examined in the two groups: control and PCOS. Further analyses were performed after a 5-year age stratification of data throughout the reproductive period. All participants signed a consent form approved by the local ethical committee.
Biomarkers of adiposity were more remarkable in African descendant PCOS women. Body weight, waist/hip ratio, fat mass, and BMI were higher in PCOS women and tended to increase at all 5 age-strata, between ≤19 and 35 years of age. Serum androgen levels decreased with aging, markedly in PCOS subjects (P < 0.01 for all age-strata comparisons), but remained elevated when compared with the levels found in controls. Carbohydrate markers, triglycerides, and total cholesterol tended to increase over time in PCOS (P < 0.01 for all age-strata comparisons). Total cholesterol also tended to increase with age in non-PCOS women (P = 0.041).
The present study has shown that the advancing age influences many features of PCOS women. Biochemical hyperandrogenism, the core criterion recommended in the current systems to define the syndrome, showed statistically significant tendencies to decrease with aging progression but did not normalize. The use of age-adjusted features for the diagnosis of PCOS are recommended.
Jana Ernst, Urszula Grabiec, Kathrin Falk, Faramarz Dehghani and Kristina Schaedlich
Studies of the last decade associated the environmental contamination by di-(2-ethylhexyl)-phthalate (DEHP) with obesity and endocrine malfunction. DEHP was found to interact with several receptors – among them are receptors of the endocannabinoid system (ECS) with high expression levels in adipose tissue. Furthermore, the correlation for BMI and body fat to the serum endocannabinoid level raises the question if the obesogenic and endocrine-disrupting DEHP effects are mediated via the ECS. We therefore characterized the ECS in a human cell model of adipogenesis using the SGBS preadipocytes to subsequently investigate if DEHP exposure affects the intrinsic ECS. The receptors of the ECS and the endocannabinoid-metabolizing enzymes were upregulated during normal adipogenesis, accompanied by an increasing secretion of the adipokines adiponectin and leptin. DEHP affected the secretion of both adipokines but not the ECS, suggesting DEHP to alter the endocrine function of adipocytes without the involvement of the intrinsic ECS.
W Liu, Y Wang, X Han, X Cai, Y Zhu, M Zhang, S Gong, J Li and L Ji
Type 1 diabetes (T1DM) is associated with a higher risk of premature death, but there are factors in certain patients with T1DM that protect them from complications and premature death. These factors had not been identified in non-Caucasian populations, so we aimed to identify factors that protect against the development of diabetic nephropathy (DN) and diabetic retinopathy (DR) in long-standing T1DM in China.
Ninety-five T1DM patients with >30 years’ duration of diabetes were enrolled in this nationwide study. Differences between groups of patients with and without complications were compared, and multivariable regression analysis was used to evaluate the relationships between candidate protective factors and the development of DN or DR.
Thirty of the participants did not have DN and the same amount did not have DR. 6/52 of participants without DN were from a rural area, whereas 11/28 of participants with DN had been born in a rural area (P = 0.005). Systolic blood pressure (SBP) was higher in participants with DN (135 ± 26 mmHg vs 121 ± 13 mmHg; P = 0.002). In participants without DR, 27/30 were married or cohabitating, and only 3/30 were single, never married, or widowed, but for those with proliferative DR (PDR), 13/26 had been married (P = 0.003). A rural or urban origin and SBP were associated with DN in the multivariable analysis.
we have shown that higher socioeconomic status, indicated by birth in an urban area, and being married or cohabitating, are accompanied by better blood pressure control and a lower risk of microvascular complications in Chinese patients with long-standing T1DM. These findings illustrate the importance of improving care for patients with T1DM in China.
Eric Seidel, Gudrun Walenda, Clemens Messerschmidt, Benedikt Obermayer, Mirko Peitzsch, Paal Wallace, Rohini Bahethi, Taekyeong Yoo, Murim Choi, Petra Schrade, Sebastian Bachmann, Gerhard Liebisch, Graeme Eisenhofer, Dieter Beule and Ute I Scholl
Mitotane is the only drug approved for the therapy of adrenocortical carcinoma (ACC). Its clinical use is limited by the occurrence of relapse during therapy. To investigate the underlying mechanisms in vitro, we here generated mitotane-resistant cell lines. After long-term pulsed treatment of HAC-15 human adrenocortical carcinoma cells with 70 µM mitotane, we isolated monoclonal cell populations of treated cells and controls and assessed their respective mitotane sensitivities by MTT assay. We performed exome sequencing and electron microscopy, conducted gene expression microarray analysis and determined intracellular lipid concentrations in the presence and absence of mitotane. Clonal cell lines established after pulsed treatment were resistant to mitotane (IC50 of 102.2 ± 7.3 µM (n = 12) vs 39.4 ± 6.2 µM (n = 6) in controls (biological replicates, mean ± s.d., P = 0.0001)). Unlike nonresistant clones, resistant clones maintained normal mitochondrial and nucleolar morphology during mitotane treatment. Resistant clones largely shared structural and single nucleotide variants, suggesting a common cell of origin. Resistance depended, in part, on extracellular lipoproteins and was associated with alterations in intracellular lipid homeostasis, including levels of free cholesterol, as well as decreased steroid production. By gene expression analysis, resistant cells showed profound alterations in pathways including steroid metabolism and transport, apoptosis, cell growth and Wnt signaling. These studies establish an in vitro model of mitotane resistance in ACC and point to underlying molecular mechanisms. They may enable future studies to overcome resistance in vitro and improve ACC treatment in vivo.
A variety of endocrine and metabolic signals regulate pituitary cell function acting through the hypothalamus-pituitary neuroendocrine axes or directly at the pituitary level. The underlying intracellular transduction mechanisms in pituitary cells are still debated. AMP-activated protein kinase (AMPK) functions as a cellular sensor of low energy stores in all mammalian cells and promotes adaptive changes in response to calorie restriction. It is also regarded as a target for therapy of proliferative disorders. Various hormones and drugs can promote tissue-specific activation or inhibition of AMPK by enhancing or inhibiting AMPK phosphorylation, respectively. This review explores the preclinical studies published in the last decade that investigate the role of AMP-activated protein kinase in the intracellular transduction pathways downstream of endocrine and metabolic signals or drugs affecting pituitary cell function, and its role as a target for drug therapy of pituitary proliferative disorders. The effects of the hypoglycemic agent metformin, which is an indirect AMPK activator, are discussed. The multiple effects of metformin on cell metabolism and cell signalling and ultimately on cell function may be either dependent or independent of AMPK. The in vitro effects of metformin may also help highlighting differences in metabolic requirements between pituitary adenomatous cells and normal cells.
Volha V Zhukouskaya, Anya Rothenbuhler, Annamaria Colao, Carolina Di Somma, Peter Kamenický, Séverine Trabado, Dominique Prié, Christelle Audrain, Anna Barosi, Christèle Kyheng, Anne-Sophie Lambert and Agnès Linglart
X-linked hypophosphatemia (XLH) is a rare disease characterized by low phosphate levels. Scientific evidence points to a link between hypophosphatemia and obesity in general population. The aim of our longitudinal observational study was to investigate the prevalence of obesity and associated factors in a large cohort of children with XLH.
We studied 172 XLH-children 5–20 years of age (113 girls/59 boys). Anthropometric parameters (weight, height, and BMI) were collected at birth and during follow-up at mean ages of 5.3, 8.2, 11.3, and 15.9 years (groups 1, 2, 3, and 4, respectively). In each group, subjects were classified based on International Obesity Taskforce (IOTF) cut off values of BMI for age and sex as overweight or obese (IOTF 25–30 or ≥30 kg/m2, respectively).
In each age-group, almost 1/3 of XLH-patients were classified as overweight or obese (29.4, 28.7, 27.5, and 36.7% in groups 1, 2, 3, and 4, respectively). Children without a XLH-family history had higher BMI-IOTF at every point of follow-up, compared to those with positive XLH-family history. Similarly, higher BMI-IOTF was significantly associated with treatment duration (23.3 ± 4.4 vs 23.8 ± 3.8 vs 25.2 ± 4.5 kg/m2, for subjects with treatment duration of <5, 5–10 and >10 years, respectively, P for trend = 0.025). Multiple regression analysis confirmed an association of treatment duration and lack of XLH-family history with higher BMI-IOTF.
One out of three of XLH-children have phenotypically unfavourable metabolic profile expressed as increased prevalence of overweight or obesity in comparison to general population. Both the lack of XLH family history and the duration of treatment increase the risk of higher BMI-IOTF. BMI should be carefully monitored in children, and later in adults, with XLH.