RESUMO
Obesity is a metabolic disorder that predisposes to numerous diseases and has become a major global public health concern. Cafeteria diet (CAF) is the animal model used for the study of obesity that more closely reflects Western diet habits. Previously, we described that CAF administration for 60 days induces obesity in female rats and their fetuses develop macrosomia. Given that, in our model, rats are not genetically modified and that obese mothers were fed standard chow during pregnancy, the aim of the current study was to test the hypothesis that obesity alters the intrauterine environment prior to pregnancy, and this may explain the exacerbated fetal weight gain. We found that uteri from obese rats during the estrous phase developed insulin resistance through mechanisms that involve the induction of uterine hypoxia and the down-regulation of the insulin receptor gene. Moreover, uterine cell proliferation was induced by obesity concomitantly with the reduction in the uterine contractile response to a ß2 AR agonist, salbutamol, and this may be consequence of the down-regulation in the uterine ß2 AR expression. We conclude that CAF-induced obesity alters the uterine environment in rats during the estrous phase and may cause the fetal macrosomia previously described by us in obese animals. The lower sensitivity of the uterus to a relaxation stimulus (salbutamol) is not a minor fact given that for implantation to occur the uterus must be relaxed for embryo nidation. Thus, the alteration in the uterine quiescence may impair implantation and, consequently, the foregoing pregnancy.
Assuntos
Obesidade/fisiopatologia , Complicações na Gravidez/etiologia , Útero/fisiologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Albuterol/farmacologia , Animais , Proliferação de Células , Dieta/efeitos adversos , Regulação para Baixo , Feminino , Regulação da Expressão Gênica , Hipóxia/etiologia , Resistência à Insulina , Obesidade/complicações , Obesidade/etiologia , Gravidez , Ratos Wistar , Receptor de Insulina/genética , Receptores Adrenérgicos/metabolismo , Contração Uterina/efeitos dos fármacos , Contração Uterina/fisiologia , Útero/fisiopatologiaRESUMO
Obesity constitutes a health problem of increasing worldwide prevalence related to many reproductive problems such as infertility, ovulation dysfunction, preterm delivery, fetal growth disorders, etc. The mechanisms linking obesity to these pathologies are not fully understood. Cafeteria diet (CAF) is the animal model used for the study of obesity that more closely reflects western diet habits. Previously we described that CAF induces obesity associated to hyperglycemia, reduced ovarian reserve, presence of follicular cysts and ovulatory impairments. The aim of the present study was to contribute in the understanding of the physiological mechanisms altered as consequence of obesity. For that purpose, female Wistar rats were fed ad libitum with a standard diet (control group) or CAF (Obese group). We found that CAF fed-rats developed obesity, glucose intolerance and insulin resistance. Ovaries from obese rats showed decreased glucose uptake and became insulin resistant, showing decreased ovarian expression of glucotransporter type 4 and insulin receptor gene expression respect to controls. These animals showed an increased follicular nitric oxyde synthase expression that may be responsible for the ovulatory disruptions and for inflammation, a common feature in obesity. Obese rats resulted subfertile and their pups were macrosomic. We conclude that obesity alters the systemic and the ovarian glucidic homeostasis impairing the reproductive outcome. Since macrosomia is a risk factor for metabolic and obstetric disorders in adult life, we suggest that obesity is impacting not only on health and reproduction but it is also impacting on health and reproduction of the offspring.
Assuntos
Dieta/efeitos adversos , Obesidade/fisiopatologia , Ovário/fisiopatologia , Animais , Distribuição da Gordura Corporal , Feminino , Teste de Tolerância a Glucose , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Homeostase , Resistência à Insulina , Óxido Nítrico Sintase/metabolismo , Obesidade/complicações , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Ovário/metabolismo , Gravidez , Ratos Wistar , Receptor de Insulina/genéticaRESUMO
Acute hyperandrogenism decreases serum P levels and induces early apoptosis of antral follicles by a mechanism mediated by the peroxisome proliferator-activated receptor gamma system and independent of the steroidogenic acute regulator protein.
Assuntos
Gonadotropina Coriônica/farmacologia , Hiperandrogenismo/fisiopatologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , PPAR gama/metabolismo , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Desidroepiandrosterona/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Hiperandrogenismo/metabolismo , Hiperandrogenismo/patologia , Folículo Ovariano/patologia , PPAR gama/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Substâncias para o Controle da Reprodução/farmacologiaRESUMO
The present study investigated the role of the N, N'-dimethylbiguanide metformin (50 mg/kg body weight in 0.05 ml water, given orally with a canulla) in preventing the adverse effects generated by hyperandrogenism on uterine function. Daily injection of dehydroepiandrosterone (DHEA: 6 mg/100 g body weight in 0.1 ml oil) for 20 consecutive days induces polycystic ovaries in BALB/c mice. In this model we found that DHEA produced alterations on uterine histology closely related to the development of pre-cancerous structures concomitantly with increased incidence of uterine apoptosis. The injection of DHEA induced a pro-inflammatory status since uterine prostaglandin (PG) F2 alpha levels and cyclooxygenase 2 were increased although PGE levels were decreased. Furthermore, DHEA promoted a pro-oxidant status since it increased nitric oxide synthase (NOS) activity and decreased superoxide dismutase and catalase activities and the antioxidant metabolite glutathione levels. DHEA also regulated the percentages of CD4+ and CD8+ T lymphocyte that infiltrate uterine tissue. When metformin was administered together with DHEA uterine histology and apoptosis did not differ when compared with controls. Therefore, metformin prevented the pro-inflammatory and pro-oxidative status generated by DHEA and restores the ratios of CD4+ and CD8+ T cells to those observed in controls. We conclude that metformin is able to restore either directly or indirectly uterine function by preventing some inflammatory and oxidative alterations produced by hyperandrogenism.