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      Effects of Obesity and Metabolic Syndrome on Steroidogenesis and Folliculogenesis in the Female Ossabaw Mini-Pig

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          Abstract

          The discrete effects of obesity on infertility in females remain undefined to date. To investigate obesity-induced ovarian dysfunction, we characterized metabolic parameters, steroidogenesis, and folliculogenesis in obese and lean female Ossabaw mini-pigs. Nineteen nulliparous, sexually mature female Ossabaw pigs were fed a high fat/cholesterol/fructose diet (n=10) or a control diet (n=9) for eight months. After a three-month diet-induction period, pigs remained on their respective diets and had ovarian ultrasound and blood collection conducted during a five-month study period after which ovaries were collected for histology, cell culture, and gene transcript level analysis. Blood was assayed for steroid and protein hormones. Obese pigs developed abdominal obesity and metabolic syndrome, including hyperglycemia, hypertension, insulin resistance and dyslipidemia. Obese pigs had elongated estrous cycles and hyperandrogenemia with decreased LH, increased FSH and luteal phase progesterone, and increased numbers of medium, ovulatory, and cystic follicles. Theca cells of obese, compared to control, pigs displayed androstenedione hypersecretion in response to in vitro treatment with LH, and up-regulated 3-beta-hydroxysteroid dehydrogenase 1 and 17-beta-hydroxysteroid dehydrogenase 4 transcript levels in response to in vitro treatment with LH or LH + insulin. Granulosa cells of obese pigs had increased 3-beta-hydroxysteroid dehydrogenase 1 transcript levels. In summary, obese Ossabaw pigs have increased transcript levels and function of ovarian enzymes in the delta 4 steroidogenic pathway. Alterations in LH, FSH, and progesterone, coupled with theca cell dysfunction, contribute to the hyperandrogenemia and disrupted folliculogenesis patterns observed in obese pigs. The obese Ossabaw mini-pig is a useful animal model in which to study the effects of obesity and metabolic syndrome on ovarian function and steroidogenesis. Ultimately, this animal model may be useful toward the development of therapies to improve fertility in obese and/or hyperandrogenemic females or in which to examine the effects of obesity on the maternal-fetal environment and offspring health.

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          Most cited references 50

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          The development of porcine models of obesity and the metabolic syndrome.

          Despite aggressive research aimed at understanding the myriad biochemical factors that are integrated to balance energy intake and expenditure to maintain normal body weight, obesity is increasing at an alarming rate, and the long-term success of prevention and intervention strategies is minimal. Because much of the scientific literature addressing obesity has originated with rodent models, there is considerable interest among researchers and funding agencies in the development of comparative animal models. Furthermore, numerous disparate results between rodent models and humans (i.e., adipsin, leptin, resistin, tumor necrosis factor-alpha, and other adipokines) have hindered the translation of rodent data into actionable technologies for humans. The pig is an exceptional restenosis model, and is emerging rapidly as a biomedical model for energy metabolism and obesity in humans because it is devoid of brown fat postnatally and because of their similar metabolic features, cardiovascular systems, and proportional organ sizes. This article highlights the current literature devoted to the development of porcine models for obesity and the metabolic syndrome, with a particular emphasis on the role of adipose tissue and adipokines in the regulation of energy balance and the inflammation associated with obesity.
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            The metabolic syndrome

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              Metabolic syndrome and coronary artery disease in Ossabaw compared with Yucatan swine.

              Metabolic syndrome (MetS), a compilation of associated risk factors, increases the risk of type 2 diabetes and coronary artery disease (CAD, atherosclerosis), which can progress to the point of artery occlusion. Stents are the primary interventional treatment for occlusive CAD, and patients with MetS and hyperinsulinemia have increased restenosis. Because of its thrifty genotype, the Ossabaw pig is a model of MetS. We tested the hypothesis that, when fed high-fat diet, Ossabaw swine develop more features of MetS, greater native CAD, and greater stent-induced CAD than do Yucatan swine. Animals of each breed were divided randomly into 2 groups and fed 2 different calorie-matched diets for 40 wk: control diet (C) and high-fat, high-cholesterol atherogenic diet (H). A bare metal stent was placed in the circumflex artery, and pigs were allowed to recover for 3 wk. Characteristics of MetS, macrovascular and microvascular CAD, in-stent stenosis, and Ca(2+) signaling in coronary smooth muscle cells were evaluated. MetS characteristics including, obesity, glucose intolerance, hyperinsulinemia, and elevated arterial pressure were elevated in Ossabaw swine compared to Yucatan swine. Ossabaw swine with MetS had more extensive and diffuse native CAD and in-stent stenosis and impaired coronary blood flow regulation compared with Yucatan. In-stent atherosclerotic lesions in Ossabaw coronary arteries were less fibrous and more cellular. Coronary smooth muscle cells from Ossabaw had impaired Ca(2+) efflux and intracellular sequestration versus cells from Yucatan swine. Therefore, Ossabaw swine are a superior model of MetS, subsequent CAD, and cellular Ca(2+) signaling defects, whereas Yucatan swine are leaner and relatively resistant to MetS and CAD.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 June 2015
                2015
                : 10
                : 6
                Affiliations
                [1 ]Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States of America
                [2 ]Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202–5120, United States of America
                INIA, SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RLK. Performed the experiments: ANF JNT MA RLK. Analyzed the data: ANF RLK. Contributed reagents/materials/analysis tools: MA MS RAN JMB RLK. Wrote the paper: ANF MA MS RAN JMB RLK.

                [¤a]

                Current address: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, United States of America

                [¤b]

                Current address: National Foundation for Fertility Research, Lone Tree, CO USA 80124, United States of America

                Article
                PONE-D-15-05838
                10.1371/journal.pone.0128749
                4457902
                26046837

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 5, Tables: 1, Pages: 18
                Product
                Funding
                This study was supported by the National Institutes of Health R21 HD060105 and K01 OD011177 ( www.nih.gov). The open access publishing fees for this article have been covered by the Texas A&M University Online Access to Knowledge (OAK) Fund, supported by the University Libraries and the Office of the Vice President for Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data is available via the Texas A&M University repository ( https://repository.tamu.edu/handle/1969.1/153767).

                Uncategorized

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