The neuronal circuits involved in energy homeostasis are being extensively explored;however, the intrinsic mechanisms underlying the regulation of these neurons are just beginning to be elucidated and will be critical for understanding disorders associated with energy homeostasis (i.e., obesity, anorexia, cachexia, etc.). These neuronal circuits are modulated by many different peripheral hormones including 17?-estradiol (E2). E2, which varies during the menstrual cycle, is anorectic leading to decreased food intake and body weight. E2 can alter homeostatic functions by activating ER? and novel G-protein coupled membrane estrogen receptors (GqmER) to alter the expression and activity of cation channels that control neuronal excitability. Hence, an emerging and significant field in neuroendocrinology within the past decade has been the convergence of membrane-initiated steroid signaling and physiological effects. The membrane-initiated events utilized by E2 involve activation of a host of known pathways that control neuronal excitability, gene expression and cellular functions. A novel transgenic strain of mice (ER? Ki/Ko) lack a functional DNA binding domain on the ER? protein and, thus exhibit no Estrogen Response Element-mediated transcription. Using these mice along with wild type and full ER? KO, we can determine the actions of ERE-dependent and ERE-independent transcription and cell signaling on energy homeostasis. Furthermore, there is growing evidence that both of these types of signaling events are potential targets for environmental estrogens (bisphenol A (BPA), alkylphenols, phytoestrogens, etc.). Therefore, environmental estrogens have a multiplicity of potential targets in the hypothalamus outside of altering normal reproductive capacity including other hypothalamic functions controlled by endogenous estrogen. Experiments outlined this application will examine the multiple receptormediated pathways that E2 (and environmental estrogens) impact energy homoeostasis and other hypothalamic functions in the hypothalamus. In the first aim, Specific Aim 3 of K99/R00, we will elucidate the effects of ERE-dependent and ERE-independent E2 signaling (ER? and/or Gq-mER) in the control of energy homeostasis and hypothalamic gene expression and if maternal exposure to environmental estrogens function through similar mechanisms.
The second aim, Specific Aim 4 of K99/R00) will examine the electrophysiological effects of exposures to environmental estrogens on POMC and NPY neuronal activity and cation channel expression both in vivo and in slice preparations. The electrophysiological effects of environmental estrogens on hypothalamic neuronal activity has not been examine previously. Since recent evidence suggests a link between developmental exposure to BPA and adult obesity, the goals of this research will address basic neurological effects of these compounds and further enhance our knowledge of the impacts environmental estrogens have on human health using novel approaches (transgenic mouse models and electrophysiological techniques) and integration with whole animal studies.

Public Health Relevance

This project will be a continuation of the research outlined in the independent aims of R00-DK-83457. Specific Aim 3 is examining the effects of 17-estradiol and environmental estrogens on energy homeostasis and hypothalamic gene expression using ovariectomized wild-type, ERa KO and ERa Ki/Ko female mice (ERa Ki/Ko mice are a transgenic strain that lack a functional DNA binding domain on the ERa protein and thus exhibit no Estrogen Response Element-mediated transcription). Specific Aim 4 is examining the membraneinitiated and nuclear-initiated effects of environmental estrogens on neuronal excitability and channel activity in POMC and NPY neurons. During the fall of 2012, we were conducting experiments outlined in Specific Aim 3 (Aim 1 of the Independent Phase). We had completed ~ 40% of the experiments when Hurricane Sandy hit the New Jersey shoreline about 100 south of Rutgers University. Here at Rutgers, we experienced power outages that lasted for 3-4 days. While the animal care facility had back-up power for certain services, the lights in every mouse room as well as the heat were not sufficiently supported by back-up. The near total darkness and temperature changes disrupted the circadian rhythms and homeostatic functions of all of the colony and especially the breeder pairs. This caused sufficient disruption to all of the breeding pairs in the mouse colony affecting not only the breeders but also all of those animals born shortly before, during and after the storm. While I was able to maintain the colony, we suffered delays in experiments due to changes in feeding behavior, maturation and in the number of robust, thriving young adults for ~ 3 months lasting well into January 2013. These deleterious effects on energy homeostasis were seen for several months, as animals born after the storm in November and December did not respond to 17-estradiol as they had prior to the storm. Therefore, I had to repeat studies well into the spring. This disruption not only delayed experiments based on the R00, some of which I described in my 2013 Progress Report, but also in the collection of data for the R01 application that was submitted June 5. This R01 is focused on the M-current and energy homeostasis, a development of the Specific Aims 1 &2 from the K99/R00. My initial plans was to submit the R01 in February, which would allow sufficient time for review, revisions, resubmission and potentially awarding of funds prior to the end of the R00 Y3 funding (5-31-14). However, the submission was delayed due to the problems with the animal colony. Furthermore, I had planned on submitting another R01 in response to PA-12-185 based off the data collected for the R00 specific aims (Specific Aim 3 &4 ~ see Research Strategy) in Feb 2014. This submission has also been pushed back to June 2014. The delays caused by Hurricane Sandy have impacted my ability to secure extramural funding prior to the completion of the R00 (5/3/14) and I am requesting one year of continuation for the R00 at the current funding level.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Transition Award (R00)
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Hyde, James F
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Rutgers University
Veterinary Sciences
Schools of Earth Sciences/Natur
New Brunswick
United States
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Vail, Gwyndolin; Roepke, Troy A (2018) Membrane-initiated estrogen signaling via Gq-coupled GPCR in the central nervous system. Steroids :
Mamounis, Kyle J; Hernandez, Michelle R; Margolies, Nicholas et al. (2018) Interaction of 17?-estradiol and dietary fatty acids on energy and glucose homeostasis in female mice. Nutr Neurosci 21:715-728
Roepke, Troy A; Yasrebi, Ali; Villalobos, Alejandra et al. (2017) Loss of ER? partially reverses the effects of maternal high-fat diet on energy homeostasis in female mice. Sci Rep 7:6381
Mamounis, Kyle J; Yasrebi, Ali; Roepke, Troy A (2017) Linoleic acid causes greater weight gain than saturated fat without hypothalamic inflammation in the male mouse. J Nutr Biochem 40:122-131
Yang, Jennifer A; Stires, Hillary; Belden, William J et al. (2017) The Arcuate Estrogen-Regulated Transcriptome: Estrogen Response Element-Dependent and -Independent Signaling of ER? in Female Mice. Endocrinology 158:612-626
Yasrebi, Ali; Rivera, Janelle A; Krumm, Elizabeth A et al. (2017) Activation of Estrogen Response Element-Independent ER? Signaling Protects Female Mice From Diet-Induced Obesity. Endocrinology 158:319-334
Gotthardt, Juliet D; Verpeut, Jessica L; Yeomans, Bryn L et al. (2016) Intermittent Fasting Promotes Fat Loss With Lean Mass Retention, Increased Hypothalamic Norepinephrine Content, and Increased Neuropeptide Y Gene Expression in Diet-Induced Obese Male Mice. Endocrinology 157:679-91
Yang, Jennifer A; Mamounis, Kyle J; Yasrebi, Ali et al. (2016) Regulation of gene expression by 17?-estradiol in the arcuate nucleus of the mouse through ERE-dependent and ERE-independent mechanisms. Steroids 107:128-38
Hu, Pu; Liu, Ji; Yasrebi, Ali et al. (2016) Gq Protein-Coupled Membrane-Initiated Estrogen Signaling Rapidly Excites Corticotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus in Female Mice. Endocrinology 157:3604-20
Roepke, Troy A; Yang, Jennifer A; Yasrebi, Ali et al. (2016) Regulation of arcuate genes by developmental exposures to endocrine-disrupting compounds in female rats. Reprod Toxicol 62:18-26

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