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Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMC ARH ) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMC ARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMC ARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.

Estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HT DRN ) to promote binge drinking. We found that female mice drank more alcohol than male mice in chronic drinking in the dark (DID) tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor α (ERα) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling. In supporting this view, 5-HT DRN neurons from naïve male mice had lower baseline firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HT DRN neurons from naïve female mice. Notably, this higher sensitivity was blunted by 17β-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERα and ERβ are expressed in 5-HT DRN neurons, whereas ERα agonist depolarizes and ERβ agonist hyperpolarizes 5-HT DRN neurons. Notably, both treatments blocked the stimulatory effects of alcohol on 5-HT DRN neurons in males, even though they have antagonistic effects on the activity dynamics. These results suggest that ERs' inhibitory effects on ethanol-induced burst firing of 5-HT DRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERα- or ERβ-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERα/β to prevent alcohol-induced activation of 5-HT DRN neurons, which in return leads to higher binge alcohol drinking., (© 2024. The Author(s).)

Estrogen receptor–α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERα vlVMH ) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ERα vlVMH neurons. We found that selective activation of ERα vlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERα vlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERα vlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed that 5-HT DRN neurons mediate the stimulatory effects of ERα vlVMH neurons on BAT thermogenesis and physical activity and that ERα expressed by DRN-projecting ERα vlVMH neurons is required for the maintenance of energy balance. Together, these findings support a model that ERα vlVMH neurons activate BAT thermogenesis and physical activity through stimulating 5-HT DRN neurons.