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

Oestrogen receptor alpha (ERα) signalling 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. ERα 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 ERα-dependent repression during male development, whereas male-biased expression of Pdyn is maintained by circulating testicular hormone in adulthood. Chemogenetic activation of ERα-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 ERα in the masculinization of neuron populations that underlie energy expenditure. The ventromedial nucleus of the hypothalamus is known to maintain energy homeostasis by controlling locomotor activity and thermogenesis. Here van Veen and Kammel et al. identified heterogeneous neuronal populations with sexually dimorphic gene expression and functions by using single-cell RNA analysis.