A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis

Jian Qiu, Martha A. Bosch, Sandra C. Tobias, Andree Krust, Sharon M. Graham, Stephanie J. Murphy, Kenneth S. Korach, Pierre Chambon, Thomas (Tom) Scanlan, Oline Ronnekleiv, Martin Kelly

Research output: Contribution to journalArticle

179 Scopus citations

Abstract

Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation, and motivated behaviors. The critical role of 17β-estradiol (E2) is evident in hypoestrogenic states (e.g., postmenopause) in which many of these functions go awry. The actions of E 2 in the brain have been attributed to the activation of estrogen receptors α and β through nuclear, cytoplasmic, or membrane actions. However, we have identified a putative membrane-associated estrogen receptor that is coupled to desensitization of GABAB and μ-opioid receptors in guinea pig and mouse hypothalamic proopiomelanocortin neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the Gαq-coupled phospholipase C-protein kinase C-protein kinase A pathway, and have established that STX is more potent than E2 in mediating this desensitization in an ICI 182, 780-sensitive manner in both guinea pig and mouse neurons. Both E2 and STX were fully efficacious in estrogen receptor α,β knock-out mice. Moreover, in vivo treatment with STX, similar to E2, attenuated the weight gain in hypoestrogenic female guinea pigs. Therefore, this membrane-delimited signaling pathway plays a critical role in the control of energy homeostasis and may provide a novel therapeutic target for treatment of postmenopausal symptoms and eating disorders in females.

Original languageEnglish (US)
Pages (from-to)5649-5655
Number of pages7
JournalJournal of Neuroscience
Volume26
Issue number21
DOIs
StatePublished - 2006

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Keywords

  • Body weight
  • GABA receptor
  • GPCR
  • Intracellular signaling
  • POMC neurons
  • Potassium channels

ASJC Scopus subject areas

  • Neuroscience(all)

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