The purpose of the present study was to screen the prognostic targets for breast cancer based on a co-expression modules analysis. The microarray dataset GSE73383 was downloaded from the Gene Expression Omnibus (GEO) database, including 15 breast cancer samples with good prognosis and 9 breast cancer samples with poor prognosis. The differentially expressed genes (DEGs) were identified with the limma package. The Database for Annotation, Visualization and Integrated Discovery was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Furthermore, the co‑expression analysis of DEGs was conducted with weighted correlation analysis. The interaction associations were analyzed with the Human Protein Reference Database and BioGRID. The protein‑protein interactions (PPI) network was constructed and visualized by Cytoscape software. A total of 491 DEGs were identified in breast cancer samples with poor prognosis compared with those with good prognosis, and they were enriched in 85 GO terms and 4 KEGG pathways. 368 DEGs were co‑expressed with others, and they were clustered into 10 modules. Module 6 was the most relevant to the clinical features, and 21 genes and 273 interaction pairs were selected out. Abnormal expression levels of required for meiotic nuclear division 5 homolog A (RMND5A) and angiopoietin‑like protein 1 (ANGPTL1) were associated with a poor prognosis. It was indicated that SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily D, member 1, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily D, member 1, dihydropyrimidinase‑like 2, RMND5A and ANGPTL1 were potential prognostic markers in breast cancer, and the cell cycle may be involved in the regulation of breast cancer.

Naringin, a natural flavanone primarily found in citrus fruits, has garnered increased attention due to its recognized antioxidative, anti-inflammatory, and cardioprotective attributes. However, the functions of naringin in regulating energy expenditure are poorly understood. In the present study, we observed that twelve weeks of naringin supplementation substantially reshaped the metabolic profile of high-fat diet (HFD)-fed mice, by inhibiting body weight gain, reducing liver weight, and altering body compositions. Notably, naringin exhibited a remarkable capacity to augment whole-body energy expenditure of the tested mice by enhancing the thermogenic activity of brown adipose tissue (BAT) and stimulating browning of inguinal white adipose tissue (iWAT). Furthermore, our results showed naringin supplementation modified gut microbiota composition, specifically increasing the abundance of Bifidobacterium and Lachnospiraceae_bacterium_28-4, while reducing the abundance of Lachnospiraceae_bacterium_DW59 and Dubosiella_newyorkensis. Subsequently, we also found naringin supplementation altered fecal metabolite profile, by significantly promoting the production of taurine, tyrosol, and thymol, which act as potent activators of thermoregulation. Interestingly, the metabolic effects of naringin were abolished upon gut microbiota depletion through antibiotic intervention, concurrently leading the disappearance of naringin-induced thermogenesis and protective actions on diet-induced obesity. This discovery revealed a novel food-driven cross-sectional communication between gut bacteria and adipose tissues. Collectively, our data indicate that naringin supplementation stimulates BAT thermogenesis, alters fat distribution, promotes the browning process, and consequently inhibits body weight gain; importantly these metabolic effects require the participation of gut bacteria.

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.

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^ARHneurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMC^ARHneurons 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.