Ovariectomy and chronic stress lead toward leptin resistance in the satiety centers and insulin resistance in the hippocampus of Sprague- Dawley rats

Aim To evaluate the changes in the expression level of gonadal steroid, insulin, and leptin receptors in the brain of adult Sprague-Dawley female rats due to ovariectomy and/or chronic stress. Methods Sixteen-week-old ovariectomized and non-ovariectomized female Sprague-Dawley rats were divided in two groups and exposed to three 10-day-sessions of sham or chronic stress. After the last stress-session the brains were collected and free-floating immunohistochemical staining was performed using androgen (AR), progesterone (PR), estrogen-β (ER-β), insulin (IR-α), and leptin receptor (ObR) antibodies. The level of receptors expression was analyzed in hypothalamic (HTH), cortical (CTX), dopaminergic (VTA/SNC), and hippocampal regions (HIPP). Results Ovariectomy downregulated AR in the hypothalamic satiety centers and hippocampus. It prevented or attenuated the stress-specific upregulation of AR in these regions. The main difference in stress response between non-ovariectomized and ovariectomized females was in PR level. Ovariectomized ones had increased PR level in the HTH, VTA, and HIPP. Combination of stressors pushed the hypothalamic satiety centers toward the rise of ObR and susceptibility to leptin resistance. When exposed to combined stressors, the HIPP, SNC and piriform cortex upregulated the expression of IR-α and the possibility to develop insulin resistance. Conclusion Ovariectomy exacerbates the effect of chronic stress by preventing gonadal receptor-specific stress response reflected in the up-regulation of AR in the satiety and hippocampal regions, while stress after ovariectomy usually raises PR. The final outcome of inadequate stress response is reflected in the upregulation of ObR in the satiety centers and IR-α in the regions susceptible to early neurodegeneration. We discussed the possibility of stress induced metabolic changes under conditions of hormone deprivatio

Primjena metformina i liraglutida utječe na strukturu hipokampusnih gangliozida u modelu štakora na dijeti obogaćenoj mastima i ugljikohidratima

Insulin resistance has many deleterious effects on the central nervous system, including the initiation and potentiation of neurodegeneration. While the pathogenesis of Alzheimer’s disease has been extensively researched with many insights into the effects of amyloids and neurofibrillary tangles, the connection between the two pathogenic entities has not yet been fully elucidated. Gangliosides are commonly found in neuronal membranes and myelin, specifically in lipid rafts that have been linked to pathological amyloidogenesis. In this study, 64 Sprague Dawley rats with equal sex distribution were separated into four sex-specific groups, as follows: control group on standard diet; group on high-fat, high-sugar diet (HFHSD); group on HFHSD treated with metformin; and group on HFHSD treated with liraglutide. Free-floating immunohistochemistry of the rat hippocampi was performed to analyze group-specific and sex-specific changes in the composition of the four most common gangliosides found in neuronal membranes and myelin sheaths, GM1, GD1a, GD1b and GT1b. The groups on HFHSD showed glucose tolerance impairment and body weight increase at the end of the experiment, whereas the groups treated with pharmacotherapeutics had better insulin sensitivity and decreases in body weight by the end of the experiment. Most changes were observed for GM1 and GD1b. Positive immunoreactivity for GM1 was observed in the male group treated with liraglutide in regions where it is not physiologically found. The changes observed following HFHSD and liraglutide treatment were suggestive of ganglioside restructuring that might have implications on pathological amyloidogenesis. Metformin treatment did not significantly alter the hippocampal ganglioside composition in either sex.Inzulinska rezistencija ima negativan učinak na središnji živčani sustav, uključujući razvoj i potencijaciju neurodegenerativnih promjena. Iako postoje brojna saznanja o patogenezi Alzheimerove bolesti u kontekstu amiloidnih depozita i neurofibrilarnih vlakana, veza između inzulinske rezistencije i Alzheimerove bolesti još uvijek nije u potpunosti razjašnjena. Gangliozidi su prisutni u membranama neurona i mijelinskim ovojnicama, osobito u sklopu lipidnih splavi, koje su identificirane kao mjesto patološke amiloidogeneze. Ukupno je 64 Sprague Dawley štakora jednake spolne distribucije podijeljeno u četiri spolno specifične skupine: kontrolnu skupinu na standardnoj dijeti, skupinu na dijeti obogaćenoj mastima i ugljikohidratima (HFHSD), skupinu na HFHSD uz liječenje metforminom te skupinu na HFHSD uz liječenje liraglutidom. Provedena je free-floating imunohistokemijska analiza promjena četiri najzastupljenija gangliozida u neuronskim membranama i mijelinskim ovojnicama: GM1, GD1a, GD1b i GT1b. Skupine na HFHSD pokazale su poremećenu toleranciju glukoze te povećanje tjelesne mase na kraju eksperimenta, dok su skupine koje su primale farmakoterapeutike pokazale poboljšanje tolerancije glukoze te smanjenje tjelesne mase na kraju eksperimenta. Najviše promjena zabilježeno je kod gangliozida GM1 i GD1b. Pozitivna imunoreaktivnost za GM1 zabilježena je kod mužjaka koji su liječeni liraglutidom i u regijama hipokampusa gdje u fiziološkim uvjetima nisu prisutni. Promjene nakon HFHSD i liječenja liraglutidom upućuju na restrukturiranje hipokampusnih gangliozida, što može imati implikacije za patološku amiloidogenezu. Liječenje metforminom nije značajno utjecalo na hipokampusnu strukturu gangliozida u oba spola

Obesity in pregnancy: a novel concept on the roles of adipokines in uterine contractility

Obesity is a global health problem even among pregnant women. Obesity alters quality of labor, such as preterm labor, prolonged labor, and higher oxytocin requirements in pregnant women. The most important factors to play a role in the altered gestational period and serve as drug targets to treat the consequences are female sexual hormones, calcium channels, adrenergic system, oxytocin, and prostaglandins. However, we have limited information about the impact of obesity on the pregnant uterine contractility and gestation time. Adipose tissue, which is the largest endocrine and paracrine organ, especially in obesity, is responsible for the production of adipokines and various cytokines and chemokines, and there are no reliable data available describing the relation between body mass index, glucose intolerance, and adipokines during pregnancy. Recent data suggest that the dysregulation of leptin, adiponectin, and kisspeptin during pregnancy contributes to gestational diabetes mellitus and pre-eclampsia. A preclinical method for obese pregnancy should be developed to clarify the action of adipokines and assess their impact in obesity. The deeper understanding of the adipokines- induced processes in obese pregnancy may be a step closer to the prevention and therapy of preterm delivery or prolonged pregnancy. Gestational weight gain is one of the factors that could influence the prenatal development, birth weight, and adiposity of newborn

Plasma Content of Glucose, C-reactive Protein, Uric Acid and Cholesterol in Male, Female and Ovariectomized Rats upon Acute and Chronic Stress – a Path for Development of Cardiovascular Diseases

To explore sex differences in cardiovascular function under stress, we analyzed plasma levels of glucose, C-reactive protein (CRP), uric acid and cholesterol in male, female and ovariectomized rats under acute and chronic stress. Glucose tolerance test (GTT) was performed in all rats before any stress was performed, as well as later in the chronic stress experiment. GTT in control animals showed the same trend as in chronically stressed. Male rats showed the highest plasma level of glucose and uric acid upon acute stress in comparison between the other two groups. Ovariectomized rats reached the highest concentration of plasma cholesterol during acute and chronic stress, respectively and also the highest plasma concentration of CRP during acute stress. Stress, as a risk factor of metabolic syndrome, affected biochemical parameters in males upon acute more than upon chronic stress, but the opposite was observed in female rats. Gender differences supported by ovariectomy show that stress managing could be affected by sexual hormones

Sex differences in oxidative stress level and antioxidative enzymes expression and activity in obese pre-diabetic elderly rats treated with metformin or liraglutide

Aim To determine the effects of metformin or liraglutide on oxidative stress level and antioxidative enzymes gene ex - pression and activity in the blood and vessels of pre-diabet - ic obese elderly Sprague-Dawley (SD) rats of both sexes. Methods Male and female SD rats were assigned to the following groups: a) control group (fed with standard ro - dent chow); b) high-fat and high-carbohydrate diet (HSHFD) group fed with HSHFD from 20-65 weeks of age; c) HSHFD+metformin treatment (50 mg/kg/d s.c.); and d) HSHFD+liraglutide treatment (0.3 mg/kg/d s.c). Oxidative stress parameters (ferric reducing ability of plasma and thiobarbituric acid reactive substances) and superoxide dis - mutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity and gene expression were determined from serum, aortas, and surface brain blood vessels (BBV). Results HSHFD increased body weight in both sexes com - pared with the control group, while liraglutide prevented this increase. Blood glucose level did not change. The lira - glutide group had a significantly increased antioxidative ca - pacity compared with the HSHFD group in both sexes. The changes in antioxidative enzymes’ activities in plasma were more pronounced in male groups. The changes in gene ex - pression of antioxidative enzymes were more prominent in microvessels and may be attributed to weight gain preven - tion. Conclusions Obesity and antidiabetic drugs caused sexrelated differences in the level of antioxidative parameters. Liraglutide exhibited stronger antioxidative effects than metformin. These results indicate that weight gain due to HSHFD is crucial for developing oxidative stress and for in - hibiting antioxidative protective mechanism

Sex-specific chronic stress response at the level of adrenal gland modified sexual hormone and leptin receptors

Aim To compare cardiometabolic risk-related biochemical markers and sexual hormone and leptin receptors in the adrenal gland of rat males, non-ovariectomized females (NON-OVX), and ovariectomized females (OVX) under chronic stress. Methods Forty six 16-week-old Sprague-Dawley rats were divided into male, NON-OVX, and OVX group and exposed to chronic stress or kept as controls. Weight, glucose tolerance test (GTT), serum concentration of glucose, and cholesterol were measured. Adrenal glands were collected at the age of 28 weeks and immunohistochemical staining against estrogen beta (ERβ), progesterone (PR), testosterone (AR), and leptin (Ob-R) receptors was performed. Results Body weight, GTT, serum cholesterol, and glucose changed in response to stress as expected and validated the applied stress protocol. Stressed males had significantly higher number of ERβ receptors in comparison to control group (P = 0.028). Stressed NON-OVX group had significantly decreased AR in comparison to control group (P = 0.007). The levels of PR did not change in any consistent pattern. The levels of Ob-R increased upon stress in all groups, but the significant difference was reached only in the case of stressed OVX group compared to control (P = 0.033). Conclusion Chronic stress response was sex specific. OVX females had similar biochemical parameters as males. Changes upon chronic stress in adrenal gland were related to an increase in testosterone receptor in females and decrease in estrogen receptor in males

Disparities and relative risk ratio of preterm birth in six Central and Eastern European centers

Aim To identify characteristic risk factors of preterm birth in Central and Eastern Europe and explore the differences from other developed countries. Method Data on 33 794 term and 3867 preterm births (<37 wks.) were extracted in a retrospective study between January 1, 2007 and December 31, 2009. The study took place in 6 centers in 5 countries: Czech Republic, Hungary (two centers), Romania, Slovakia, and Ukraine. Data on historical risk factors, pregnancy complications, and special testing were gathered. Preterm birth frequencies and relevant risk factors were analyzed using Statistical Analysis System (SAS) software. Results All the factors selected for study (history of smoking, diabetes, chronic hypertension, current diabetes, preeclampsia, progesterone use, current smoking, body mass index, iron use and anemia during pregnancy), except the history of diabetes were predictive of preterm birth across all participating European centers. Preterm birth was at least 2.4 times more likely with smoking (history or current), three times more likely with preeclampsia, 2.9 times more likely with hypertension after adjusting for other covariates. It had inverse relationship with the significant predictor body mass index, with adjusted risk ratio of 0.8 to 1.0 in three sites. Iron use and anemia, though significant predictors of preterm birth, indicated mixed patterns for relative risk ratio. Conclusion Smoking, preeclampsia, hypertension and body mass index seem to be the foremost risk factors of preterm birth. Implications of these factors could be beneficial for design and implementation of interventions and improve the birth outcome

Impact of ovariectomy, high fat diet, and lifestyle modifications on oxidative/antioxidative status in the rat liver

Aim To estimate the impact of high fat diet and estrogen deficiency on the oxidative and antioxidative status in the liver of the ovariectomized rats, as well as the ameliorating effect of physical activity or consumption of functional food containing bioactive compounds with antioxidative properties on oxidative damage in the rat liver. Methods The study was conducted from November 2012 to April 2013. Liver oxidative damage was determined by lipid peroxidation levels expressed in terms of thiobarbituric acid reactive substances (TBARS), while liver antioxidative status was determined by catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) activities, and glutathione (GSH) content. Sixty-four female Wistar rats were divided into eight groups: sham operated and ovariectomized rats that received either standard diet, high fat diet, or high fat diet supplemented with cereal selenized onion biscuits or high fat diet together with introduction of physical exercise of animals. Results High fat diet significantly increased TBARS content in the liver compared to standard diet (P = 0.032, P = 0.030). Furthermore, high fat diet decreased the activities of CAT, GR, and GST, as well as the content of GSH (P < 0.050). GPx activity remained unchanged in all groups. Physical activity and consumption of cereal selenized onion biscuits showed protective effect through increased GR activity in sham operated rats (P = 0.026, P = 0.009), while in ovariectomized group CAT activity was increased (P = 0.018) in rats that received cereal selenized onion biscuits. Conclusion Feeding rats with high fat diet was accompanied by decreased antioxidative enzyme activities and increased lipid peroxidation. Bioactive compounds of cereal selenized onion biscuits showed potential to attenuate the adverse impact of high fat diet on antioxidative statu