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Integrating hypothalamic ERα signaling with peripheral metabolic and reproductive tissues
Holly Ingraham
We propose to systemically assess the physiological and genomic consequences of hypothalamic ERα signaling in the mediobasal hypothalamus (MBH). In women, loss of estrogen correlates with increased risk for obesity and Type 2 diabetes. Hence, the precipitous drop in hormone replacement therapy, coupled with longer lifespans, suggests that the risk for metabolic diseases will continue to rise for the large number of post-menopausal women in the U.S.

Recent studies from our lab (Correa et al, 2015, Cell Reports) and others have established the importance of central estrogen signaling via ERα in regulating sex-specific aspects of metabolism and reproduction in mouse models. Although the role of central estrogen signaling in modulating female metabolism and reproduction has been appreciated for decades, a comprehensive strategy to understand the molecular aspects of estrogen signaling in the brain is lacking. Newer technology allows us to address this challenge.

We will focus on two peripheral target tissues, BAT and ovary, that both integrate the aggregate effects of central ERα signaling in a gender-specific manner. Two approaches will be taken that use stereotaxic delivery of AAV-viral vectors into the MBH to manipulate estrogen signaling. The first will acutely and conditionally knockout ERα in the VMHvl (or ARC) in intact and OVX adult females. The second will artificially activate ERα neurons in the VMHvl using chemogenetics via DREADD technology. The molecular and metabolic changes in the VMHvl, BAT and ovary will be assessed using Transcriptome, Translatome and Metabalome Profiling. We will also leverage a newly created reporter mouse (Ucp1-Luc2 transgene) that allows for real time imaging of brown adipose tissue (BAT) activity in females. Quality control will be used to select the best 3-4 experimental samples for further processing to obtain final data sets. Once datasets are generated and curated, top candidate hits will be validated by standard methods. Such data will provide new mechanistic insights into the gender-specific integration of central ERα signaling with metabolic and reproductive endpoint organs.