Hypothalamic α7 nicotinic acetylcholine receptor (α7nAChR) is downregulated by TNFα‐induced Let‐7 overexpression driven by fatty acids

• Published in: The FASEB journal 2023-09, Vol.37 (9), p.e23120-n/a
• Main Authors: Simino, Laís A. P., Baqueiro, Mayara N., Panzarin, Carolina, Lopes, Priscilla K. F., Góis, Mariana M., Simabuco, Fernando M., Ignácio‐Souza, Letícia M., Milanski, Marciane, Ross, Michael G., Desai, Mina, Torsoni, Adriana S., Torsoni, Marcio A.
• Format: Article
• Language: English
• Subjects: alpha7 nicotinic acetylcholine receptor; cytokines, tumor necrosis factor‐alpha; diet, high fat; fatty acids; hypothalamus; microRNAs; obesity
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202300439RR

The α7nAChR 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 α7nAchR 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 α7nAChR levels, accompanied by hypothalamic fatty acids and TNFα content. Hypothalamic neuronal cells exposed to fatty acids presented higher Let‐7a and TNFα levels and lower Chrna7 expression, but when the cells were pre‐treated with TLR4 inhibitor, Let‐7a, TNFα, and Chrna7 were rescued to normal levels. Thus, the fatty acids overload trigger TNFα‐induced Let‐7 overexpression in hypothalamic neuronal cells, which negatively regulates α7nAChR, an event that can be related to hyperphagia and obesity predisposition in mice. (A) Mice acutely exposed to an obesogenic diet have higher TNFα and Let‐7a, while lower Chrna7 levels in the hypothalamus, as well as the hypothalamic neuronal cells exposed to fatty acids overload. (B) In vitro assays confirmed that Let‐7a can directly regulate Chrna7 levels. (C) When the hypothalamic neuronal cells exposed to fatty acids overload are pre‐treated with a TLR4 inhibitor, Let‐7a, TNFα, and Chrna7 levels are rescued to normal levels. Thus, fatty acids overload may trigger TNFα‐induced Let‐7 overexpression, which, in turn, can downregulate α7nAChR.