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 E₂ 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 GABA_B 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.