The obesity epidemic in the United States is advancing at an accelerated pace. It is estimated that by 2015, 41% of U.S. adults will be obese. Obesity is associated with diminished reproductive performance as manifested by menstrual cycle irregularities, anovulation and a higher risk of obstetrical complications. In ovulatory women, an increase in BMI over 29 kg/m2 by one unit has been shown to result in a 4 percent reduction in the likelihood of conception. Decreased central reproductive drive is present in regularly cycling obese women as demonstrated by diminished levels of gonadotropins and sex steroids. This relative hypogonadotropic hypogonadism of obesity is only partially understood. Vervet monkeys (Chlorocebus aethiops) develop obesity and its associated metabolic profile in a manner very similar to humans, based upon study of a fully pedigreed and genotyped colony of more than 400 individuals (the Vervet Research Colony). Heritability analyses of this colony support the notion that patterns of obesity in vervets are heritable, as they are among humans. Furthermore, the ovarian cycle in the vervet is well characterized and very similar to humans. This study aims to establish a mechanistic model of obesity as a direct cause of adverse reproductive hormone dynamics. To accomplish this goal, pair-wise assessments will be conducted before and after acquisition of diet-induced obesity. Adult female vervet monkeys will be fed an obesity-promoting diet for 1 year and compared with a control group that will be fed regular diet. Paired assessments of hypothalamic, pituitary, and ovarian markers will be done. To test the hypothesis that obesity decreases pituitary sensitivity to GnRH, frequent blood sampling studies will be performed for a detailed evaluation of LH pulsatility and response to GnRH. To test the hypothesis that obesity dampens GnRH pulsatility, hypothalamic responsiveness to N-Methyl-D-aspartic acid will be assessed. To test the hypothesis that obesity causes corpus luteum insufficiency, differential gene profiling will be conducted on corpus luteum tissue removed by luteectomy. The results of this study will facilitate understanding of the influence of obesity on the hypothalamic-pituitary-ovarian axis. Additionally, this will provide an appropriate platform to approach the mechanistic aspects of this association by creating reproductive derangements with diet-induced obesity.
In this application, we propose to establish an animal model of obesity as a direct cause of reproductive hormone abnormalities. We will test the hormonal production at several levels of regulation of the body's systems, including the hypothalamus, the pituitary gland and the ovary. The results of this study have the potential to further improve our understanding of how obesity affects female reproduction.
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