Neuronal miR-29a protects from obesity in adult mice

Ma, Yuan; Murgia, Nicola; Liu, Yu; Li, Zixuan; Sirakawin, Chaweewan; Konovalov, Ruslan; Kovzel, Nikolai; Xu, Yang; Kang, Xuejia; Tiwari, Anshul; Mwangi, Patrick Malonza; Sun, Dianjun; Erfle, Holger; Konopka, Witold; Lai, Qingxuan; Najam, Syeda Sadia; Vinnikov, Ilya A.

doi:10.1016/j.molmet.2022.101507

Cited by 18 publications

(26 citation statements)

References 39 publications

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“…Iterative dividing the group of oligonucleotides supplemented to ARH led us to the identification of miR-15a-5p which was capable to attenuate the obesity phenotype in a dose-dependent manner (Figure 2). Thus, our studies revealed and validated several microRNAs regulating energy homeostasis: miR-103-3p (10), miR-29a-3p (25), miR-15a-5p (current work) and, potentially, miR-320-3p demonstrating a significant, but seemingly irrelevant attenuation of weight gain detected only at two time points after surgery (Figure 2A). The latter effects have not been studied further in this work and require further validation in the future.…”

Section: Discussionsupporting

confidence: 69%

“…Indeed, both weight gain and fat pad weights in DicerCKO animals were attenuated upon treatment with the Group 1 mimics mixture (Figures 1B-D) suggesting a protective metabolic role of (at least some) microRNAs from this microRNA mixture. Accordingly, miR-103-3p and miR-29a-3p from this group had already revealed their protective functions following our in vitro analyses (10,25).…”

Section: Resultsmentioning

confidence: 63%

“…Further research to address the roles of non-coding RNAs in specific hypothalamic populations and identify the target(s) of miR-15a and other microRNAs might pave the way towards developing novel metabolic disorders-targeting therapeutics. As previously mentioned ( 25 ), these must be aimed towards microRNA targets thus providing more specificity as opposed to microRNA-directed therapeutics which might exert high off-target rates and hence potential side effects. Another important consideration about reducing the side effects relates to the fact that POMC neurons are able to acquire therapeutics directly from the 3rd ventricle, thus easing the therapeutic development and decreasing the final concentrations of the compounds.…”

Section: Discussionmentioning

confidence: 99%

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In Vivo Reductionist Approach Identifies miR-15a Protecting Mice From Obesity

Murgia

Najam

et al. 2022

Front. Endocrinol.

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Obesity is a growing medical and social problem worldwide. The control of energy homeostasis in the brain is achieved by various regions including the arcuate hypothalamic nucleus (ARH). The latter comprises a number of neuronal populations including the first order metabolic neurons, appetite-stimulating agouti-related peptide (AgRP) neurons and appetite-suppressing proopiomelanocortin (POMC) neurons. Using an in vivo reductionist approach and POMCCre-dependent CRISPR-Cas9, we demonstrate that miR-15a-5p protects from obesity. Moreover, we have identified Bace1, a gene previously linked to energy metabolism imbalance, as a direct target of miR-15a-5p. This work warrants further investigations of non-coding RNA-mediated regulation of energy homeostasis and might contribute to the development of novel therapeutic approaches to treat metabolic diseases.

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Section: Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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In Vivo Reductionist Approach Identifies miR-15a Protecting Mice From Obesity

Murgia

Najam

et al. 2022

Front. Endocrinol.

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“…Cas9 mediated off-target editing can be reduced by limiting the time Cas9 or the gRNA remains active in cells. This can be accomplished through the use of self-inactivating Cas9 vectors ( Moore et al, 2014 ; Ma et al, 2022 ), or by the use of inducible expression systems that transiently express Cas9 or the gRNA ( Davis et al, 2015 ; Zetsche et al, 2015 ; de Solis et al, 2016 ). Other approaches are to use the Cas9 nickase to create two single stranded cuts close together on opposing DNA strands ( Mali et al, 2013a ; Ran et al, 2013 ).…”

Section: Fidelity and Efficiency Of Clustered Regularly Interspersed ...mentioning

confidence: 99%

RISC-y Business: Limitations of Short Hairpin RNA-Mediated Gene Silencing in the Brain and a Discussion of CRISPR/Cas-Based Alternatives

Goel

Ploski

2022

Front. Mol. Neurosci.

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Manipulating gene expression within and outside the nervous system is useful for interrogating gene function and developing therapeutic interventions for a variety of diseases. Several approaches exist which enable gene manipulation in preclinical models, and some of these have been approved to treat human diseases. For the last couple of decades, RNA interference (RNAi) has been a leading technique to knockdown (i.e., suppress) specific RNA expression. This has been partly due to the technology’s simplicity, which has promoted its adoption throughout biomedical science. However, accumulating evidence indicates that this technology can possess significant shortcomings. This review highlights the overwhelming evidence that RNAi can be prone to off-target effects and is capable of inducing cytotoxicity in some cases. With this in mind, we consider alternative CRISPR/Cas-based approaches, which may be safer and more reliable for gene knockdown. We also discuss the pros and cons of each approach.

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“…Furthermore, another study has demonstrated that up regulation of miR-204-5p expression in brown adipose tissue of offspring born to obese mothers leads to enhanced white adipogenic commitment 14 . Few studies to date have explored the role of miRNAs in the regulation of hypothalamic energy sensing [15][16][17][18] , and none have examined the potential contribution of miRNAs to programming of long-term hypothalamic function by the perinatal environment.…”

Section: Introductionmentioning

confidence: 99%

Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food

Furigo

Pantaleão

Almeida-Faria

et al. 2022

Preprint

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In utero exposure to maternal obesity programs a susceptibility to develop obesity. Animal models have shown that offspring obesity is often preceded by increased food intake, however, the mechanisms that mediate these changes are not understood. Using a mouse model of maternal diet-induced obesity we observed increased intake specifically of a high-fat pellet in adult offspring of obese mothers. Through small RNA sequencing, we identified programmed overexpression of miR-505-5p in the hypothalamus of offspring of obese mothers that is established in the fetus, and confirmed in vitro that fatty acid exposure increases expression of miR-505-5p. Pulsed SILAC analysis demonstrated protein targets of miR-505-5p are enriched in pathways involved in fatty acid metabolism. These include key components of neuronal fatty acid sensing, such as Cpt1a, that are implicated in BMI regulation in human genetic studies. Over-expression of miR-505-5p decreased neuronal fatty acid uptake and metabolism in vitro. Importantly, intra-cerebroventricular injection of a miR-505-5p mimic in mice resulted in increased high-fat pellet intake. Collectively these data suggest that maternal obesity induces over-expression of miR-505-5p in offspring hypothalamus, resulting in altered fatty acid sensing and increased intake of high-fat diet. This represents a novel mechanism by which maternal obesity programs obesity in offspring.

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Neuronal miR-29a protects from obesity in adult mice

Cited by 18 publications

References 39 publications

In Vivo Reductionist Approach Identifies miR-15a Protecting Mice From Obesity

In Vivo Reductionist Approach Identifies miR-15a Protecting Mice From Obesity

RISC-y Business: Limitations of Short Hairpin RNA-Mediated Gene Silencing in the Brain and a Discussion of CRISPR/Cas-Based Alternatives

Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food

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