Histone H1 non-autonomously promotes lipolysis in depressive Drosophila

Depression, a prevalent mental disorder, is influenced by genetic materials and environmental factors and is often associated with weight loss, though the underlying molecular mechanisms remain unclear. Here, we performed RNA-seq on Drosophila models of depression induced by drug treatment. We found that reduced histone acetylation correlates with the specific upregulation of linker histone H1 in the brain. Remarkably, conditional overexpression of H1 in the brain, simulating drug-induced H1 elevation, led to similar gene downregulation patterns and resulted in a depressive phenotype. Moreover, both drug-treated and H1-overexpressing Drosophila displayed weight loss. Interestingly, we observed that H1 is non-autonomously required for lipid droplet homeostasis in the fat body of adult flies. Furthermore, depressive Drosophila exhibited elevated AKH signaling, promoting lipolysis, while H1 did not directly affect AKH signaling. Finally, we found that H1 preferentially binds and suppresses the transcription of rk, encoding an upstream regulator of AKH signaling. Together, these findings reveal a molecular mechanism linking depression with weight loss in animal models. Overall design: We observed the decrease of acetylation and increased of histone H1 protein in depressed flies triggered by the Levodopa, then we performed the RNA-seq to detect the transcription profiles in the depressed flies triggered by Levo, as well as the conditional H1 overexpression to see wethere the histone H1 is required and sufficient for the depression