It is difficult to differentiate the various roles of visceral adiposity, insulin resistance, and hyperandrogenism on reproductive dysfunction. The goals of my studies are to understand the mechanism by which obesity related signals impact reproductive function. Our laboratory has developed a diet induced obesity (DIO) model of female infertility that shares many of the features of PCOS, infertility and hyperandrogenism in the setting of obesity. Insulin and androgen may contribute to infertility independently or work together in a vicious cycle. Our preliminary data suggest that while peripheral energy storage tissues exhibit insulin resistance in obesity, resulting in elevated insulin levels, the tissues of the reproductive axis, particularly the pituitary and ovary, remain insulin sensitive. The elevated insulin levels, therefore, result in elevated signaling in reproductive tissues which contributes to the pathophysiology.
In Aim 1, the major proximal components of the insulin signaling system including IR and IRS isoforms will be studied in the pituitary and ovary of lean and DIO mice and the acute effects of insulin will be explored. Theca cell-specific insulin receptor KO mice (ThIRKO) will be used to study the role for insulin signaling in the ovary in normal development and function and in mediating infertility in DIO and in order to probe the physiologically and pathophysiologically relevant signaling pathways mediating the effects of insulin in the ovary which include regulating androgen synthesis. Androgen is also elevated in our DIO model, which may also contribute to insulin resistance and infertility. Therefore, this hypothesis will be directly tested in Aim 2 by measuring the insulin sensitivity of the pituitary in lean mice treated with T, or in DIO mice treated with T antagonists. To directly assess the effects of T on the pituitary and ovary, gonadotroph and ovarian theca cell specific androgen receptor KO mice will be produced (PitARKO and ThARKO, respectively). Studies for reproductive functionality and steroidogenesis in normal fed animals, and for the response to the DIO paradigm will be conducted. Information gained from these studies will provide insight into the insulin-androgen dependent mechanisms underlying the association between obesity and the pathophysiological activation of the reproductive axis in adult women as well as the complex interactions among insulin, androgens and obesity in PCOS.

Public Health Relevance

In this proposal, we will attempt to define the complex interactions of insulin and androgens on the development of obesity induced infertility. We hope to uncover the mechanism that underlies the development of infertility in women with metabolic dysfunction such as frequently is observed in PCOS.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Transition Award (R00)
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No Study Section (in-house review) (NSS)
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Eisenberg, Esther
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Johns Hopkins University
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Wang, Zhiqiang; Shen, Mingjie; Xue, Ping et al. (2018) Female Offspring From Chronic Hyperandrogenemic Dams Exhibit Delayed Puberty and Impaired Ovarian Reserve. Endocrinology 159:1242-1252
Ma, Yaping; Andrisse, Stanley; Chen, Yi et al. (2017) Androgen Receptor in the Ovary Theca Cells Plays a Critical Role in Androgen-Induced Reproductive Dysfunction. Endocrinology 158:98-108
Andrisse, Stanley; Childress, Shameka; Ma, Yaping et al. (2017) Low-Dose Dihydrotestosterone Drives Metabolic Dysfunction via Cytosolic and Nuclear Hepatic Androgen Receptor Mechanisms. Endocrinology 158:531-544
DiVall, Sara A; Herrera, Danny; Sklar, Bonnie et al. (2015) Insulin receptor signaling in the GnRH neuron plays a role in the abnormal GnRH pulsatility of obese female mice. PLoS One 10:e0119995
Wu, Sheng; Divall, Sara; Nwaopara, Amanda et al. (2014) Obesity-induced infertility and hyperandrogenism are corrected by deletion of the insulin receptor in the ovarian theca cell. Diabetes 63:1270-82
Wu, Sheng; Chen, Yi; Fajobi, Temi et al. (2014) Conditional knockout of the androgen receptor in gonadotropes reveals crucial roles for androgen in gonadotropin synthesis and surge in female mice. Mol Endocrinol 28:1670-81