Neuronal miR-29a protects from obesity in adult mice

• 主要な著者: Yuan Ma (著者), Nicola Murgia (著者), Yu Liu (著者), Zixuan Li (著者), Chaweewan Sirakawin (著者), Ruslan Konovalov (著者), Nikolai Kovzel (著者), Yang Xu (著者), Xuejia Kang (著者), Anshul Tiwari (著者), Patrick Malonza Mwangi (著者), Donglei Sun (著者), Holger Erfle (著者), Witold Konopka (著者), Qingxuan Lai (著者), Syeda Sadia Najam (著者), Ilya A. Vinnikov (著者)
• フォーマット: 図書
• 出版事項: Elsevier, 2022-07-01T00:00:00Z.
• 主題: article
• オンライン･アクセス: Connect to this object online.

要約

Objective: Obesity, a growing threat to the modern society, represents an imbalance of metabolic queues that normally signal to the arcuate hypothalamic nucleus, a critical brain region sensing and regulating energy homeostasis. This is achieved by various neurons many of which developmentally originate from the proopiomelanocortin (POMC)-expressing lineage. Within the mature neurons originating from this lineage, we aimed to identify non-coding genes in control of metabolic function in the adulthood. Methods: In this work, we used microRNA mimic delivery and POMCCre-dependent CRISPR-Cas9 knock-out strategies in young or aged mice. Importantly, we also used CRISPR guides directing suicide cleavage of Cas9 to limit the off-target effects. Results: Here we found that mature neurons originating from the POMC lineage employ miR-29a to protect against insulin resistance obesity, hyperphagia, decreased energy expenditure and obesity. Moreover, we validated the miR-29 family as a prominent regulator of the PI3K-Akt-mTOR pathway. Within the latter, we identified a direct target of miR-29a-3p, Nras, which was up-regulated in those and only those mature POMCCreCas9 neurons that were effectively transduced by anti-miR-29 CRISPR-equipped construct. Moreover, POMCCre-dependent co-deletion of Nras in mature neurons attenuated miR-29 depletion-induced obesity. Conclusions: Thus, the first to our knowledge case of in situ Cre-dependent CRISPR-Cas9-mediated knock-out of microRNAs in a specific hypothalamic neuronal population helped us to decipher a critical metabolic circuit in adult mice. This work significantly extends our understanding about the involvement of neuronal microRNAs in homeostatic regulation.

記述事項

2212-8778
10.1016/j.molmet.2022.101507