Fertility depends on proper neuroendocrine regulation of the hypothalamic-pituitary-gonadal axis. Metabolic disorders, including obesity, are often characterized by hyperinsulinemia and associated with reduced fertility in women. Production of gonadotropin hormones critical for steroidogenesis, gametogenesis and ovulation is also disturbed in these disorders. The overall goal of this application is to determine whether gonadotropin gene expression is regulated by forkhead transcription factors in pituitary gonadotrope cells. FoxO proteins are regulated by insulin signaling and thus, may be an important regulatory link between metabolic status and fertility. FoxOs regulate diverse cellular functions, such as apoptosis, stress resistance and metabolism, but their role in the neuroendocrine regulation of reproduction has not been extensively explored. Our preliminary results indicate that FoxO1 is expressed in pituitary gonadotrope cells and that FoxO1 phosphorylation and cellular localization is regulated by insulin in these cells. Our preliminary studies also show that FoxO1 suppresses basal and GnRH induction of luteinizing hormone and follicle-stimulating hormone. Our hypothesis is that the FoxO1 transcription factor suppresses gonadotropin synthesis in pituitary gonadotrope cells and that insulin signaling relieves this suppression by rendering FoxO1 transcriptionally inactive. In this proposal, we will utilize novel approaches to study mechanisms of FoxO1 transcriptional regulation of gonadotropin synthesis in vitro and in vivo.
In Specific Aim 1, a pituitary-specific knockout mouse model will be used to determine whether FoxO1 expression in the gonadotrope is necessary for fertility and whether FoxO1 plays a role in obesity-related infertility.
In Specific Aim 2, biochemical and tissue cell culture models will be used to characterize mechanisms of FoxO1 regulation of gonadotropin production.
Specific Aim 3 will address mechanisms of insulin signal transduction via FoxO1 in gonadotrope cells and determine if disruption of insulin regulation of FoxO1 impacts fertility using a conditionally active FoxO1 transgenic mouse model. Results from this proposal have the potential to answer fundamental questions regarding the role of FoxO1 in gonadotropin production and provide insight into broad mechanisms of hormonal control of fertility. Understanding these mechanisms may be relevant for the development of novel contraceptive methods or infertility treatments. Potential applications could also lead to new directions in treating a range of disorders that can result from malfunction in gonadotropin production, such as amenorrhea, precocious puberty, ideopathic hypogonadism, and polycystic ovarian syndrome. Funding of this proposal will also allow the PI, as an Early-Stage Investigator, to establish a fully-independent research program in the field of reproductive endocrinology.
Project Narrative This research project has particular relevance to the growing epidemic of obesity in women of child-bearing age. Obesity is associated with increased reproductive disorders including early onset of puberty, menstrual irregularities, pregnancy complications, and infertility due to anovulation, spontaneous abortions, and polycystic ovarian syndrome. Since obesity is also associated with alterations in gonadotropin hormone production, it is vital that we identify and characterize the mechanisms of gonadotropin synthesis to provide insight into the etiology of obesity-related infertility and its treatment.
|Skarra, Danalea V; Hernández-Carretero, Angelina; Rivera, Alissa J et al. (2017) Hyperandrogenemia Induced by Letrozole Treatment of Pubertal Female Mice Results in Hyperinsulinemia Prior to Weight Gain and Insulin Resistance. Endocrinology 158:2988-3003|
|Kelley, Scott T; Skarra, Danalea V; Rivera, Alissa J et al. (2016) The Gut Microbiome Is Altered in a Letrozole-Induced Mouse Model of Polycystic Ovary Syndrome. PLoS One 11:e0146509|
|Kauffman, Alexander S; Thackray, Varykina G; Ryan, Genevieve E et al. (2015) A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice. Biol Reprod 93:69|
|Skarra, Danalea V; Thackray, Varykina G (2015) FOXO1 is regulated by insulin and IGF1 in pituitary gonadotropes. Mol Cell Endocrinol 405:14-24|
|Thackray, Varykina G (2014) Fox tales: regulation of gonadotropin gene expression by forkhead transcription factors. Mol Cell Endocrinol 385:62-70|
|Park, Chung Hyun; Skarra, Danalea V; Rivera, Alissa J et al. (2014) Constitutively active FOXO1 diminishes activin induction of Fshb transcription in immortalized gonadotropes. PLoS One 9:e113839|
|Skarra, Danalea V; Arriola, David J; Benson, Courtney A et al. (2013) Forkhead box O1 is a repressor of basal and GnRH-induced Fshb transcription in gonadotropes. Mol Endocrinol 27:1825-39|
|Benson, Courtney A; Kurz, Troy L; Thackray, Varykina G (2013) A human FSHB promoter SNP associated with low FSH levels in men impairs LHX3 binding and basal FSHB transcription. Endocrinology 154:3016-21|
|Breen, Kellie M; Thackray, Varykina G; Hsu, Tracy et al. (2012) Stress levels of glucocorticoids inhibit LH?-subunit gene expression in gonadotrope cells. Mol Endocrinol 26:1716-31|
|Arriola, David J; Mayo, Susan L; Skarra, Danalea V et al. (2012) FOXO1 transcription factor inhibits luteinizing hormone ? gene expression in pituitary gonadotrope cells. J Biol Chem 287:33424-35|
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