Fasting-induced miR-7a-5p in AgRP neurons regulates food intake
The molecular control of feeding after fasting is essential for maintaining energy homeostasis, and overfeeding usually leads to obesity. RNA interference has been clinically successful in managing diseases, and the identification of a feeding-regulated microRNA (miRNA), which remains a challenge, could be a strategy for combating obesity. By performing a comprehensive genome-wide microRNA screening in the arcuate nucleus of the hypothalamus (ARC) of fasted mice and ad libitum mice, we found a significant increase in miR-7a-5p levels after fasting. miR-7a-5p was highly expressed in the ARC, and inhibition of miR-7a-5p specifically in AgRP neurons reduced food intake and body weight gain. miR-7a-5p inhibited S6K1 gene expression by binding to its 3'-UTR. Furthermore, the reduction of food intake by anti-miR-7a-5p was partially reversed by the downregulated mechanistic target of rapamycin complex 1 (mTOR1)/ribosomal S6 kinase 1 (S6K1) signaling in the AgRP neurons. Importantly, intracerebroventricular administration of the miR-7a-5p inhibitor could reduce food intake and body weight. Collectively, our findings suggest miR-7a-5p as an orexigenic factor in AgRP neurons and a potential novel target for obesity treatment. Overall design: A comprehensive genome-wide miRNA screening in the arcuate nucleus of the hypothalamus (ARC) of fasted mice and ad libitum mice was performed. Through intracerebral virus injections, intracerebroventricular injections, and miRNA sponge technology, miR-7a-5p was inhibited specifically in AgRP neurons and in the central nervous system, and metabolic phenotypes were monitored. Quantitative Real-time PCR, Western blotting, and luciferase reporter assay were used to investigate the mechanisms underlying miR-7a-5p's regulation of food intake.