Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation

Brain estrogen receptor α (ERα) signaling plays a vital role in regulating energy homeostasis and adipose tissue metabolism. It has been demonstrated that ERα is abundantly expressed in the ventrolateral region of the ventromedial hypothalamus (vlVMH), a sex-dimorphic structure that directly modulates brown adipose tissue (BAT) thermogenesis. We previously showed that an ERαvlVMH-originated neural circuit responds to changes in ambient temperature and nutritional states, suggesting a potential role of this neural circuit in metabolic adaptation. Here, we found that chronic activation of ERαvlVMH neurons prevents diet-induced obesity (DIO), which is associated with increased BAT thermogenesis and core temperature. Additionally, ERαvlVMH activation induces torpor-like phenotypes in fasted females. Conversely, chronic inhibition of ERαvlVMH neurons increases adiposity and decreases baseline BAT temperature. Notably, ERαvlVMH inhibition also impairs cold-induced food intake and BAT thermogenesis, resulting in lethal phenotypes during chronic cold exposure. Post hoc histology analysis revealed that ERαvlVMH inhibition induces adipose tissue whitening. Finally, we explored the anatomical distribution of ERαvlVMH downstream neural circuitries. Anterograde tracing revealed ERαvlVMH-originated projections to the medial preoptic area (MPOA), dorsal raphe nucleus (DRN), and substantia nigra (SNR). Interestingly, transsynaptic retrograde tracing further demonstrated that these brain regions send projections to inguinal white adipose tissue (iWAT), suggesting potential ERαvlVMH-originated circuits involved in adipose tissue adaptation. Chronic inhibition of ERαvlVMH→DRN circuit impaired cold-induced thermogenesis in females only, whereas chemogenetic activation of ERαvlVMH→MPOA circuit reduced thermogenic activity during cold exposure. These findings suggest that these circuits exert opposing effects and that ERαvlVMH-originated pathways regulate adipose tissue adaptation to environmental challenges in a sex-specific manner. Together, these findings support a model in which environmental challenges trigger ERαvlVMH activation to modulate fat-specific outputs and regulate adipose tissue adaptation to environmental challenges.​