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Genes Associated with Membrane-Initiated Signaling of Estrogen and Energy Homeostasis

Departments of Physiology and Pharmacology (T.A.R., C.X., M.A.B., T.S.S., M.J.K., O.K.R.), and Anesthesiology and Perioperative Medicine (O.K.R.), and Division of Neuroscience (M.A.B., O.K.R.), Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon 97239-3089

Address all correspondence and requests for reprints to: Oline K. Rønnekleiv or Martin J. Kelly, Department of Physiology and Pharmacology, Mail Code: L334, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239. E-mail: ronnekle{at}ohsu.edu or kellym{at}ohsu.edu, respectively.

During the reproductive cycle, fluctuations in circulating estrogens affect multiple homeostatic systems controlled by hypothalamic neurons. Two of these neuronal populations are arcuate proopiomelanocortin and neuropeptide Y neurons, which control energy homeostasis and feeding. Estradiol modulates these neurons either through the classical estrogen receptors (ERs) to control gene transcription or through a G protein-coupled receptor (mER) activating multiple signaling pathways. To differentiate between these two divergent ER-mediated mechanisms and their effects on homeostasis, female guinea pigs were ovariectomized and treated systemically with vehicle, estradiol benzoate (EB) or STX, a selective mER agonist, for 4 wk, starting 7 d after ovariectomy. Individual body weights were measured after each injection day for 28 d, at which time the animals were euthanized, and the arcuate nucleus was microdissected. As predicted, the body weight gain was significantly lower for EB-treated females after d 5 and for STX-treated females after d 12 compared with vehicle-treated females. Total arcuate RNA was extracted from all groups, but only the vehicle and STX-treated samples were prepared for gene microarray analysis using a custom guinea pig gene microarray. In the arcuate nucleus, 241 identified genes were significantly regulated by STX, several of which were confirmed by quantitative real-time PCR and compared with EB-treated groups. The lower weight gain of EB-treated and STX-treated females suggests that estradiol controls energy homeostasis through both ER and mER-mediated mechanisms. Genes regulated by STX indicate that not only does it control neuronal excitability but also alters gene transcription via signal transduction cascades initiated from mER activation.