Hypothalamic 7 nicotinic acetylcholine receptor (7nAChR) is downregulated by TNF-induced Let-7 overexpression driven by fatty acids

The a7nAChR is crucial to the anti-inflammatory reflex, and to the expression of neuropeptides that control food intake, but its expression can be decreased by environmental factors. We aimed to investigate whether microRNA modulation could be an underlying mechanism in the a7nAchR downregulation in mouse hypothalamus following a short-term exposure to an obesogenic diet. Bioinformatic analysis revealed Let-7 microRNAs as candidates to regulate Chrna7, which was confirmed by the luciferase assay. Mice exposed to an obesogenic diet for 3 days had increased Let-7a and decreased a7nAChR levels, accompanied by hypothalamic fatty acids and TNFa content. Hypothalamic neuronal cells exposed to fatty acids presented higher Let-7a and TNFa levels and lower Chrna7 expression, but when the cells were pre-treated with TLR4 inhibitor, Let-7a, TNFa, and Chrna7 were rescued to normal levels. Thus, the fatty acids overload trigger TNFa-induced Let-7 overexpression in hypothalamic neuronal cells, which negatively regulates a7nAChR, an event that can be related to hyperphagia and obesity predisposition in mice.