Obesity has become a global epidemic, and it is a major risk factor for other metabolic disorders such as type 2 diabetes and cardiometabolic disease. Accumulating evidence indicates that there is sex-specific metabolic protection and disease susceptibility. For instance, in both clinical and experimental studies, males are more likely to develop obesity, insulin resistance, and diabetes. In line with this, males tend to have more visceral white adipose tissue (WAT) and less brown adipose tissue (BAT) thermogenic activity, both leading to an increased incidence of metabolic disorders. This female-specific fat distribution is partially mediated by sex hormone estrogens. Specifically, hypothalamic estrogen signaling plays a vital role in regulating WAT distribution, WAT beiging, and BAT thermogenesis. These regulatory effects on adipose tissue metabolism are primarily mediated by the activation of estrogen receptor alpha (ERα) in neurons, which interacts with hormones and adipokines such as leptin, ghrelin, and insulin. This review discusses the contribution of adipose tissue dysfunction to obesity and the role of hypothalamic estrogen signaling in preventing metabolic diseases with a particular focus on the VMH, the central regulator of energy expenditure and glucose homeostasis.

The ovarian hormone estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms for estrogen-induced binge drinking are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HTDRN) to promote binge drinking. We used the drinking in the dark (DID) behavioral test in mice to mimic binge drinking in humans. We found that female mice drank more alcohol than male mice in chronic DID tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor alpha (ERalpha) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling in binge alcohol drinking. In supporting this view, 5-HTDRN neurons from naive male mice had lower baseline neuronal firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HTDRN neurons from naive female mice. Notably, this higher sensitivity was blunted by 17bata-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERalpha and ERbeta are expressed in 5-HTDRN neurons, whereas ERalpha agonist propyl pyrazole triol (PPT) depolarizes 5-HTDRN neurons and ERbeta agonist diarylpropionitrile (DPN) hyperpolarizes 5-HTDRN neurons. Notably, both PPT and DPN treatments blocked the stimulatory effects of alcohol on 5-HTDRN neurons in males, despite the fact that they have antagonistic effects on the activity dynamics of 5-HTDRN neurons. These results suggest that the inhibitory effects of ERs on ethanol-induced burst firing of 5-HTDRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERalpha- or ERbeta-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERalpha/beta to prevent alcohol-induced activation of 5-HTDRN neurons, which in return leads to higher binge alcohol drinking.