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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...
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Published in: | Molecular metabolism (Germany) 2022-07, Vol.61, p.101507-101507, Article 101507 |
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Main Authors: | , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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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.
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•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. |
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ISSN: | 2212-8778 2212-8778 |
DOI: | 10.1016/j.molmet.2022.101507 |