| Summary: | 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 <i>Npy</i> transcription in hypothalamic neurons by inducing oxidative stress. We hypothesized that hypothalamic microRNAs (miRNAs), a class of small non-coding RNAs, could directly regulate <i>Npy</i> gene expression by binding the 3′ untranslated region (UTR). Five predicted <i>Npy</i>-targeting miRNA candidates were uncovered through TargetScan and were detected in <i>Npy</i>-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 <i>Npy</i>-targeting miRNAs using miRNA mimics, and we found that miR-143-3p, miR-140-5p, miR-29b-1-5p, and let-7b-3p altered <i>Npy</i> expression in the murine hypothalamic cell lines. Importantly, miR-143-3p targets the mouse <i>Npy</i> 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 <i>Npy</i>, emphasizing the involvement of miRNAs in the NPY system and providing an alternative target for control of NPY levels.
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