- Our PhD student Yuan Ma and co-authors have found that deletion of miR-29a in mature PomcCre neurons leads to insulin resistance and hyperphagic obesity.
- For the first time, such a drastic protective metabolic effect of a single microRNA within a mature population of hypothalamic neurons was detected.
- In-depth studies of the metabolic effects of Nras and other targets of this and other microRNAs in these neurons might help to develop therapeutic strategies.
Neuronal miR-29a protects from obesity in adult mice
Ma Y., Murgia N., Liu Y., Li Z., Sirakawin C., Konovalov R., Kovzel N., Xu Y., Kang X., Tiwari A., Mwangi P.M., Sun D., Erfle H., Konopka W., Lai Q., Najam S.S. and Vinnikov I.A.✉
Molecular Metabolism, https://doi.org/10.1016/j.molmet.2022.101507: 101507.
Abstract: 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. Here we found that mature neurons originating from this lineage employ miR-29a to protect against obesity, hyperphagia and insulin resistance, as demonstrated by POMCCre-dependent CRISPR-Cas9 knock-out strategy in young or aged mice. Moreover, we showed that miR-29 family is 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. This work significantly extends our understanding about the involvement of hypothalamic microRNAs in homeostatic regulation.
- 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.
- POMCCre-restricted deletion of miR-29a causes cell-autonomous Nras up-regulation leading to obesity associated with both energy intake and expenditure.
- POMCCre-restricted knock-out of Nras, a direct target of miR-29a-3p, attenuates obesity in mice.