The Effects of Estrogens on Neural Circuits That Control Temperature.

Declining and variable levels of estrogens around the time of menopause are associated with a suite of metabolic, vascular, and neuroendocrine changes. The archetypal adverse effects of perimenopause are vasomotor symptoms, which include hot flashes and night sweats. Although vasomotor symptoms are routinely treated with hormone therapy, the risks associated with these treatments encourage us to seek alternative treatment avenues. Understanding the mechanisms underlying the effects of estrogens on temperature regulation is a first step toward identifying novel therapeutic targets. Here we outline findings in rodents that reveal neural and molecular targets of estrogens within brain regions that control distinct components of temperature homeostasis. These insights suggest that estrogens may alter the function of multiple specialized neural circuits to coordinate the suite of changes after menopause. Thus, defining the precise cells and neural circuits that mediate the effects of estrogens on temperature has promise to identify strategies that would selectively counteract hot flashes or other negative side effects without the health risks that accompany systemic hormone therapies.

Hypothalamic estrogen receptor alpha establishes a sexually dimorphic regulatory node of energy expenditure.

Estrogen receptor a (ERa) signaling in the ventromedial hypothalamus (VMH) contributes to energy homeostasis by modulating physical activity and thermogenesis. However, the precise neuronal populations involved remain undefined. Here, we describe six neuronal populations in the mouse VMH by using single-cell RNA transcriptomics and in situ hybridization. ERa is enriched in populations showing sex biased expression of reprimo (Rprm), tachykinin 1 (Tac1), and prodynorphin (Pdyn). Female biased expression of Tac1 and Rprm is patterned by ERa-dependent repression during male development, whereas male biased expression of Pdyn is maintained by circulating testicular hormone in adulthood. Chemogenetic activation of ERa positive VMH neurons stimulates heat generation and movement in both sexes. However, silencing Rprm gene function increases core temperature selectively in females and ectopic Rprm expression in males is associated with reduced core temperature. Together these findings reveal a role for Rprm in temperature regulation and ERa in the masculinization of neuron populations that underlie energy expenditure.