Validation of the obese Ossabaw miniature pig as a model of the obese polycystic ovary syndrome phenotype with concomitant metabolic syndrome: exploration of polycystic ovary syndrome pathophysiology using in vivo and in vitro

polycystic ovary syndrome;Metabolic syndrome;obesity;Ossabaw pig

Newell-Fugate, Anne

关键词: polycystic ovary syndrome;    Metabolic syndrome;    obesity;    Ossabaw pig;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/42187/Anne_Newell-Fugate.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive age women and has received substantial research time and financial support over the past few decades. Despite on-going research efforts, the etiology of this disease has not been elucidated. Many pre and post-natally androgenized animal models exist for this disorder but none completely recapitulate both the reproductive and metabolic features of the obese phenotype of PCOS with concomitant metabolic syndrome (MetS). Moreover, although PCOS is believed to arise from an interaction of heritable and non-heritable factors, there is no concrete evidence that in utero or environmental exposure to androgens forms the basis for the non-heritable aspect of its pathogenesis. This Ph.D. dissertation focused on the validation of the obese Ossabaw (OSS) pig as an animal model for the obese phenotype of PCOS with concomitant MetS. Unlike the currently available animal models for PCOS, this animal model incorporates both heritable (thrifty genotype breed) and non-heritable (obesogenic diet) components. The main findings of this work were that when OSS pigs were fed an excess calorie high fat/cholesterol/fructose diet: 1) both OSS sows and gilts developed android obesity and metabolic perturbations, including but not limited to dyslipidemia, hypertension and glucose intolerance, which met the Rotterdam Diagnostic Criteria for MetS; 2) both OSS sows and gilts developed persistent post-ovulatory size ovarian cysts; 3) both OSS sows (androstenedione only) and gilts (androstenedione and DHEAS) became hyperandrogenemic; 4) both OSS sows and gilts developed protracted estrous cycle length; 5) both OSS sows and gilts developed increased numbers of medium (3.5-6.5 mm) and large (6.5-12.5 mm) size follicles during the luteal phase of the estrous cycle; 6) OSS sows had increased LH and decreased progesterone serum concentrations; 6) OSS gilts had decreased LH and increased FSH serum concentrations throughout the estrous cycle as well as increased progesterone serum concentrations during the luteal phase only; 7) OSS sows responded to a long-term GnRH agonist superovulation protocol similarly to OSS sows on a control diet; 8) the theca cells of OSS gilts did not demonstrate basal differences in the gene expression of steroidogenic enzymes but did respond to in vitro LH stimulation with increased production of androstenedione; 9) OSS gilts had an increased androgen:estrogen ratio in the follicular fluid and demonstrated down regulation of estrogen controlled genes on oocytes; 10) OSS gilts responded to an in vivo androgen challenge similarly to OSS gilts on a control diet. These findings demonstrate that both the obese OSS sow and gilt are excellent animal models for obesity and MetS in humans. There is also evidence that each of these animal model variations manifest some of the features of the obese phenotype of PCOS. However, based on the current evidence generated by this Ph.D. research neither of these model animals completely recapitulates all of the reproductive features of the obese phenotype of PCOS. It is possible that the obese OSS sow and/or gilt may be better suited as models of the effects of obesity on reproductive and endocrine physiology. Future research that examines the role of the adrenal gland and adipose tissue as well as expands on current knowledge of theca, granulosa, and oocyte physiology in this model animal will characterize further the molecular mechanisms underlying the biochemical and physical attributes of the obese OSS pig.