Hypothalamic proopiomelanocortin (POMC) neurons have been shown to play a critical role in energy homeostasis. The long-range goal of the proposed research is to define the differences in signaling mechanism(s) by which estrogen (E2) modulates opiomelanocortin tone and subsequently homeostatic functions in a sex-specific manner. Understanding the actions of E2 on POMC neurons will provide insight into fundamental differences between females and males in the control of feeding, and as a consequence eating disorders, which are more common in females after puberty. The biological bases for these discrepancies are unknown, but likely involve hypothalamic POMC neurons and their response to E2 and serotonin (5HT) in a sex-specific manner. We have found that E2 can rapidly disinhibit female POMC neurons via uncoupling mu-opioid and GABAB receptors, and have identified a putative membrane-associated E2 receptor (mER) that is Gq-coupled to a phospholipase C-protein kinase C-protein kinase A pathway, which is very similar to what has been described for serotonin 5TH2A/C receptors. In addition, we have synthesized a new SERM, STX that specifically targets this novel E2 signaling pathway. Rapid signaling by E2 (STX) has a number of downstream targets including uncoupling G i,o coupled neurotransmitter receptors from K+ (GIRK) channels in POMC neurons, which enhances neuronal activity. Our hypothesis is that sex differences in the control of feeding and energy homeostasis are due, in part, to the greater efficacy of E2 in females versus males to dis-inhibit POMC neurons and that the mER and 5HT2c intracellular signaling pathways converge in POMC neurons in a sex specific manner. In this proposal, we seek to elucidate the cellular cascades activated by E2 and serotonin in both sexes. We will use a unique range of cellular, molecular and chemical tools to characterize the signaling pathways in POMC neurons and its functional consequences in both male and females.
The specific aims are: (1) To test the efficacy of STX in gonadectomized animals to uncouple GABAB, f-opioid and 5HTiA receptors from K+ channels in POMC neurons. (2) To delineate the 5HT2A/c signaling pathway and determine its convergence with the mER signaling pathway in POMC neurons. (3) To measure the effects of STX on food intake and energy metabolism in gonadectomized male and female guinea pigs. (4) To measure the effects of STX on POMC neurons in wild type and ER? deficient mice. The results from these studies will not only help to elucidate sex differences in estrogen and serotonin signaling pathways in hypothalamic POMC neurons that control feeding and energy homeostasis, but potentially will allow the development of SERMs for treatment of eating disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK068098-01A1
Application #
6929466
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Sato, Sheryl M
Project Start
2005-03-01
Project End
2009-01-31
Budget Start
2005-03-01
Budget End
2006-01-31
Support Year
1
Fiscal Year
2005
Total Cost
$332,200
Indirect Cost
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Qiu, Jian; Nestor, Casey C; Zhang, Chunguang et al. (2016) High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons. Elife 5:
Padilla, Stephanie L; Qiu, Jian; Soden, Marta E et al. (2016) Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state. Nat Neurosci 19:734-741
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Qiu, Jian; Zhang, Chunguang; Borgquist, Amanda et al. (2014) Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab 19:682-93

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