Preoptic Anterior Hypothalamus Estrogen Signaling Controls Energy and Temperature Homeostasis

An ovarian hormone, estrogen, has been shown to act on the preoptic anterior hypothalamus (POA) to modulate temperature and energy homeostasis. However, the underlying neural mechanism is still largely less known. Interestingly, we found that POA neurons express high levels of estrogen receptor α (ERα) and β (ERβ), and a subpopulation of POA neurons co-express ERα and ERβ (ERα/βPOA). We showed that ERα agonist stimulates ERα/βPOA neurons, whereas ERβ agonist inhibits ERα/βPOA neurons. Estrogen17β-estradiol (E2) showed mixed actions in the ERα/βPOA neurons, presumably caused by the counterbalance between ERα and ERβ. This dynamic counterbalance may lead to distinct effects of E2 in regulating temperature and energy balance depending on temperature or nutritional status. Consistently, chemogenetic activation of ERαPOA decreased food intake, brown adipose tissue (BAT) thermogenesis, and body temperature, mimicking warm-induced adaptation. Conversely, inhibition of ERβPOA neurons increases food intake, BAT thermogenesis, and body temperature, mimicking cold-induced adaptation. In conclusion, these results support a model that ERα/βPOA neurons service as an integrating center for the estrogenic regulation of temperature and energy homeostasis. Disclosure P.Luo: None. P.Xu: None. X.Yang: None. B.Feng: None. H.Ye: None. N.Antony: None. L.Carrillo-sáenz: None. V.C.Torres irizarry: None. B.T.Layden: Consultant; Bayer Inc. Y.He: None. Funding National Institutes of Health (R01DK123098, P30DK020595 to P.X.), (P20GM135002, R01DK129548 to Y.H.), (T32AA026577 to V.C.T.I.); American Heart Association (915789 to V.C.T.I.), (20POST35120600 to Y.H.); U.S. Department of Defense (W81XWH-20-1-0075 to P.X