The hyperandrogenemia that often occurs in association with polycystic ovary syndrome and the typical high-fat/high-calorie Western-style diet (WSD) can both result in obesity and metabolic and reproductive dysfunction. It is unclear whether these effects are independent of obesity, or if hyperandrogenemia and WSD together exert synergistic effects on metabolic control and reproductive competence. This is a critical issue for young pre/peripubertal girls who are subject to hyperandrogenemia in the context of a WSD. Adipose tissue is a prime candidate for a site of integration of the separate and combined effects of hyperandrogenemia and WSD;it is responsive to both androgens and WSD, and capable of elaborating adipocytokines that can (a) produce a feedback enhancement of inflammatory responses in adipose tissue itself, as well as (b) influencing other organs, including the reproductive system, though classical endocrine and neuroendocrine mechanisms. This project will examine the consequences of carefully controlled testosterone exposure and WSD, singly and in combination, in a unique longitudinal study of prepubertal female nonhuman primates. The study will also include an arm in which testosterone and WSD are removed in order to ascertain the persistence of androgen effects, which will inform the design of therapeutic approaches to attenuate the consequences of hyperandrogenemia and high-fat/high-caloric diet. We hypothesize that hyperandrogenemia and WSD induce synergistic, dysfunctional effects on female adipose tissue function that are manifested as altered cellular morphology, insulin responsiveness, inflammatory status, and adipocytokine secretion. To address this hypothesis, we propose the following specific aims: 1. To determine the effects of hyperandrogenemia and WSD on adipocyte tissue morphology, differentiation state, and insulin action by exploiting our recently developed approaches for ex vivo analysis of adipose explants. 2. To determine the effects of hyperandrogenemia and WSD on adipose inflammation, fibrosis, vascularization, and adipocytokine secretion. 3. To determine the reversibility of the effects of hyperandogenemia on adipose tissue function.
Many girls produce higher-than-normal levels of the male sex hormone testosterone at puberty, which can have serious consequences such as an increased risk of diabetes and infertility. This usually occurs in combination with consumption of a high-fat/high-calorie diet, which can also have serious health consequences even before obesity develops. This project will determine if the combination of testosterone and a high-fat/calorie diet together has much more severe effects on disease risk than either alone.
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|McGee, W K; Bishop, C V; Pohl, C R et al. (2014) Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys. Am J Physiol Endocrinol Metab 306:E1292-304|
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|Amin, Marli; Simerman, Ariel; Cho, Michele et al. (2014) 21-Hydroxylase-derived steroids in follicles of nonobese women undergoing ovarian stimulation for in vitro fertilization (IVF) positively correlate with lipid content of luteinized granulosa cells (LGCs) as a source of cholesterol for steroid synthesis. J Clin Endocrinol Metab 99:1299-306|
|Heneidi, Saleh; Simerman, Ariel A; Keller, Erica et al. (2013) Awakened by cellular stress: isolation and characterization of a novel population of pluripotent stem cells derived from human adipose tissue. PLoS One 8:e64752|
|Chazenbalk, Gregorio; Singh, Prapti; Irge, Dana et al. (2013) Androgens inhibit adipogenesis during human adipose stem cell commitment to preadipocyte formation. Steroids 78:920-6|
|Varlamov, Oleg; Chu, Michael P; McGee, Whitney K et al. (2013) Ovarian cycle-specific regulation of adipose tissue lipid storage by testosterone in female nonhuman primates. Endocrinology 154:4126-35|
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