Loading…

Neuronal miR-29a protects from obesity in adult mice

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 t...

Full description

Saved in:
Bibliographic Details
Published in:Molecular metabolism (Germany) 2022-07, Vol.61, p.101507-101507, Article 101507
Main Authors: Ma, Yuan, Murgia, Nicola, Liu, Yu, Li, Zixuan, Sirakawin, Chaweewan, Konovalov, Ruslan, Kovzel, Nikolai, Xu, Yang, Kang, Xuejia, Tiwari, Anshul, Mwangi, Patrick Malonza, Sun, Donglei, Erfle, Holger, Konopka, Witold, Lai, Qingxuan, Najam, Syeda Sadia, Vinnikov, Ilya A.
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. 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. 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. 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. [Display omitted] •Delivery of miR-29a-3p to the arcuate hypothalamic nucleus attenuates obesity.•Knock-out of genes in mature neurons by Cre-dependent CRISPR/Cas9 technique involving Cas9-cleaving sgRNAs to limit off-target effects.•Deletion of miR-29a in mature PomcCre neurons leads to early-onset insulin resistance and later to hyperphagia and decreased energy expenditure.•POMCCre-restricted deletion of miR-29a causes cell-autonomous Nras up-regulation leading to obesity.•POMCCre-restricted knock-out of Nras, a direct target of miR-29a-3p, attenuates obesity in mice.
ISSN:2212-8778
2212-8778
DOI:10.1016/j.molmet.2022.101507