Abstract
The hypothalamus is a vital regulator of energy homeostasis. Orexigenic neuropeptide Y (NPY) neurons within the hypothalamus can stimulate feeding and suppress energy expenditure, and dysregulation of these neurons may contribute to obesity. We previously reported that bisphenol A (BPA), an endocrine disruptor with obesogenic properties, alters Npy transcription in hypothalamic neurons by inducing oxidative stress. We hypothesized that hypothalamic microRNAs (miRNAs), a class of small non-coding RNAs, could directly regulate Npy gene expression by binding the 3' untranslated region (UTR). Five predicted Npy-targeting miRNA candidates were uncovered through TargetScan and were detected in Npy-expressing hypothalamic neuronal cell models and hypothalamic neuronal primary cultures. BPA dysregulated the expression of a number of these hypothalamic miRNAs. We examined the effects of putative Npy-targeting miRNAs using miRNA mimics, and we found that miR-143-3p, miR-140-5p, miR-29b-1-5p, and let-7b-3p altered Npy expression in the murine hypothalamic cell lines. Importantly, miR-143-3p targets the mouse Npy 3' UTR, as detected using a luciferase construct containing the potential 3' UTR binding sites. Overall, this study established the first hypothalamic miRNA that directly targets the 3' UTR of mouse Npy, emphasizing the involvement of miRNAs in the NPY system and providing an alternative target for control of NPY levels.