Palmitate alters miR-2137 and miR-503-5p to induce orexigenic Npy in hypothalamic neuronal cell models: Rescue by oleate and docosahexaenoic acid.

MicroRNAs (miRNAs) are short noncoding RNA implicated in the pathogenesis of obesity. One cause of obesity is excess exposure to the saturated fatty acid palmitate that can alter miRNA levels in the periphery. Palmitate also promotes obesity by acting on the hypothalamus, the central coordinator of energy homeostasis, to dysregulate hypothalamic feeding neuropeptides and induce ER stress and inflammatory signaling. We hypothesized that palmitate would alter hypothalamic miRNAs that control genes involved in energy homeostasis thereby contributing to the obesity-promoting effects of palmitate. We found that palmitate upregulated 20 miRNAs and downregulated six miRNAs in the orexigenic NPY/AgRP-expressing mHypoE-46 cell line. We focused on delineating the roles of miR-2137 and miR-503-5p, as they were strongly up- and downregulated by palmitate, respectively. Overexpression of miR-2137 increased Npy mRNA levels and downregulated Esr1 levels, while increasing C/ebpβ and Atf3 mRNA. Inhibiting miR-2137 had the opposite effect, except on Npy, which was unchanged. The most downregulated miRNA by palmitate, miR-503-5p, negatively regulated Npy mRNA levels. Exposure to the unsaturated fatty acids oleate or docosahexaenoic acid completely or partially blocked the effects of palmitate on miR-2137 and miR-503-5p as well as Npy, Agrp, Esr1, C/ebpβ and Atf3. MicroRNAs may therefore contribute to palmitate actions in dysregulating NPY/AgRP neurons. Effectively combating the deleterious effects of palmitate is crucial to help prevent or reduce the impact of obesity.