Hypothalamic actions of estrogens in the regulation of energy and glucose homeostasis

Estrogens are a group of steroid hormones that exert a key role in female sexual and reproductive development and function. Produced primarily in the ovaries, estrogens influence many different aspects of physiology such as temperature homeostasis, feeding behavior, locomotor activity and glucose homeostasis by acting at the central nervous system. In particular, these endocrine factors interact with different hypothalamic nuclei in order to exert an increase in body temperature, anorectic effect, increased locomotion and improved glucose handling. Estrogenic actions can be mediated through several receptors, including the estrogen receptor-α (ERα), estrogen receptor-β (ERβ) and G protein-coupled estrogen receptor 1 (GPER1). Among these, ERα is well established to be one key receptor mediating estrogenic actions on energy balance partially through its transcriptional activity as a nuclear receptor. In addition to the transcriptional activities, E2 can also trigger rapid signaling cascades in the hypothalamus where AMPK, cAMP, PI3K, mTOR and ceramides, have all been implicated to mediate metabolic actions of E2. Moreover, E2 can induce in neurons super-fast excitations through the membrane-bound ERα. A putative membrane ER coupled to Gq (Gq-mER) has been proposed to mediate E2 actions on G protein-gated inwardly rectifying potassium GIRK, on the small conductance calcium-activated potassium (SK) currents, and on the ATP-sensitive potassium (K_ATP) currents in hypothalamic neurons. Finally, a chloride ion channel (Clic1) was recently proposed to mediate E2-induced excitation of ERα-expressing neurons in the hypothalamus. This article will review recent advances in understanding these neurobiological processes regulated by estrogens and the associated molecular mechanism.