The long range goal of this application is to understand the mechanisms by which estrogen and environmental estrogens affect hypothalamic functions such as energy homeostasis. There is an obesity epidemic in the US and understanding the etiology of any and all factors that contribute to expression of obesity is critical for treatment of this disorder. Therefore, the goal of the mentored projects is to understand how estradiol affects energy homeostasis through multiple membrane-initiated mechanisms that include the control of neuronal excitability through an estradiol-responsive membrane GPCR (mER) and control of gene expression in arcuate neurons through both ERa- and mER-mediated mechanisms. Estradiol is known to control energy homeostasis through ERa and mER because STX, a selective ligand for the mER, attenuates body weight gain post-ovariectomy. Estradiol also alters neuronal excitability of POMC arcuate neurons through the mER. One potential mER-mediated mechanism for the effects of estradiol is modulation of a non-inactivating, sub-threshold K+ current that tempers the excitability of POMC (M-current). To detennine if modulation of the M-current by estradiol plays a role in these effects, I will first measure the expression and activity of the KCNQ/M-current in POMC and NPY neurons from oil- and estradiol-treated females using qRT-PCR in pooled single cells and electrophysiology. Second, I will measure the effects of acute (via mER) estradiol treatment on the electrophysiological properties of the M-current in POMC and NPY neurons using whole cell patch recordings. The independent phase will build on the techniques learned during the mentored phase and examine the role of membrane-initiated and ERE-independent estrogen signaling in hypothalamic functions and determine whether environmental estrogens activate these same pathways in their effects.
The first aim will determine the role of ERE-independent signaling in the control of energy homeostasis and hypothalamic gene regulation by estradiol and bisphenol A using wild-type, aERKO and ERalpha KI/KO mice models.
The final aim will detennine the electrophysiological effects of bisphenol A on arcuate POMC and NPY neurons that control energy homeostasis.

Public Health Relevance

The mentored phase may directly impact the health of women (esp. post-menopausal women) since STX, the selective ligand for the membrane estrogen receptor, is a potential lead compound for an non-traditional hormone replacement therapy and treatment of obsesity disorders. Finally, the independent phase will address the potential mechanisms that environmental estrogens can impact hypothalamic functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
4R00DK083457-03
Application #
8235454
Study Section
Special Emphasis Panel (NSS)
Program Officer
Hyde, James F
Project Start
2011-09-01
Project End
2014-05-31
Budget Start
2011-09-01
Budget End
2012-05-31
Support Year
3
Fiscal Year
2011
Total Cost
$248,287
Indirect Cost
Name
Rutgers University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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
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
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
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
Yang, Jennifer A; Yasrebi, Ali; Snyder, Marisa et al. (2016) The interaction of fasting, caloric restriction, and diet-induced obesity with 17?-estradiol on the expression of KNDy neuropeptides and their receptors in the female mouse. Mol Cell Endocrinol 437:35-50
Yasrebi, Ali; Hsieh, Anna; Mamounis, Kyle J et al. (2016) Differential gene regulation of GHSR signaling pathway in the arcuate nucleus and NPY neurons by fasting, diet-induced obesity, and 17?-estradiol. Mol Cell Endocrinol 422:42-56

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