Adiponectin, a metabolic hormone secreted by adipocytes, can cross the blood-brain barrier to act on neurons in different brain regions, including those involved in stress-related disorders. Here we show that dopamine neurons in the ventral tegmental area (VTA) express adiponectin receptor 1 (AdipoR1). Intra-VTA infusion of adiponectin or the adiponectin mimetic AdipoRon in wild-type mice decreases basal dopamine neuron population activity and firing rate and reverses the restraint stress-induced increase in dopamine neuron activity and anxiety behavior. Adiponectin haploinsufficiency leads to increased dopamine neuron firing and anxiety behavior under basal conditions. Ablation of AdipoR1 specifically from dopamine neurons enhances neuronal and anxiogenic responses to restraint stress. The effects of intra-VTA infusion of adiponectin on neuronal activity and behavior were abolished in mice lacking AdipoR1 in dopamine neurons. These observations indicate that adiponectin can directly modulate VTA dopamine neuron activity and anxiety behavior, and that AdipoR1 is required for adiponectin-induced inhibition of dopamine neurons and anxiolytic effects. These results strengthen the idea of adiponectin as a key biological factor that links metabolic syndrome and emotional disorders.

No abstract

There is growing evidence that alternative splicing (AS) plays an important role in cancer development. However, a comprehensive analysis of AS signatures in kidney renal clear cell carcinoma (KIRC) is lacking and urgently needed. It remains unclear whether AS acts as diagnostic biomarkers in predicting the prognosis of KIRC patients. In the work, gene expression and clinical data of KIRC were obtained from The Cancer Genome Atlas (TCGA), and profiles of AS events were downloaded from the SpliceSeq database. The RNA sequence/AS data and clinical information were integrated, and we conducted the Cox regression analysis to screen survival‐related AS events and messenger RNAs (mRNAs). Correlation between prognostic AS events and gene expression were analyzed using the Pearson correlation coefficient. Protein‐protein interaction analysis was conducted for the prognostic AS‐related genes, and a potential regulatory network was built using Cytoscape (version 3.6.1). Meanwhile, functional enrichment analysis was conducted. A prognostic risk score model is then established based on seven hub genes (KRT222, LENG8, APOB, SLC3A1, SCD5, AQP1, and ADRA1A) that have high performance in the risk classification of KIRC patients. A total 46,415 AS events including 10,601 genes in 537 patients with KIRC were identified. In univariate Cox regression analysis, 13,362 survival associated AS events and 8,694 survival‐specific mRNAs were detected. Common 3,105 genes were screen by overlapping 13,362 survival associated AS events and 8,694 survival‐specific mRNAs. The Pearson correlation analysis suggested that 13 genes were significantly correlated with AS events (Pearson correlation coefficient >0.8 or <−0.8). Then, We conducted multivariate Cox regression analyses to select the potential prognostic AS genes. Seven genes were identified to be significantly related to OS. A prognostic model based on seven genes was constructed. The area under the ROC curve was 0.767. In the current study, a robust prognostic prediction model was constructed for KIRC patients, and the findings revealed that the AS events could act as potential prognostic biomarkers for KIRC.