Fat mass and obesity-associated protein regulates RNA methylation associated with depression-like behavior in mice
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Abstract
Post-transcriptional modifications of RNA, such as RNA methylation, can epigenetically regulate behavior, for instance learning and memory. However, it is unclear whether RNA methylation plays a critical role in the pathophysiology of major depression disorder (MDD). Here, we report that expression of the fat mass and obesity associated gene (FTO), an RNA demethylase, is downregulated in the hippocampus of patients with MDD and mouse models of depression. Suppressing Fto expression in the mouse hippocampus results in depression-like behaviors in adult mice, whereas overexpression of FTO expression leads to rescue of the depression-like phenotype. Epitranscriptomic profiling of N6-methyladenosine (m 6 A) RNA methylation in the hippocampus of Fto knockdown (KD), Fto knockout (cKO), and FTO-overexpressing (OE) mice allows us to identify adrenoceptor beta 2 ( Adrb2 ) mRNA as a target of FTO. ADRB2 stimulation rescues the depression-like behaviors in mice and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal SIRT1 expression by c-MYC. Our findings suggest that FTO is a regulator of a mechanism underlying depression-like behavior in mice.
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Lack of the FTO gene impacts anxiety-depression-like behavior in mice.
“Lack of the FTO gene impacts anxiety-depression-like behavior in mice.360”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [360]
The Results section, “FTO mediates depression-like behaviors in the hippocampus,” reports that hippocampal Fto knockdown or knockout induced depression-like behaviors in mice. The same section explicitly reports no significant change in anxiety-like behaviors, so the anxiety part of the claim is not supported. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe m6A demethylase gene ALKBH5 variant rs12936694 showed an allelic association and genotypic association with MDD.
“The m6A demethylase gene ALKBH5 variant rs12936694 showed an allelic association and genotypic association with MDD.360,363”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [360]
The Results section reports lower ALKBH5 expression in blood from patients with MDD, not an association between an ALKBH5 variant and MDD. Searches for rs12936694 and for allelic or genotypic associations found no passage addressing the claimed variant; the indexed passages provide no page numbers. (LLM, conf=0.76)
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“The FTO variant rs9939609 in human trials was associated with a lower risk of developing MDD. 358 A correlation is reported between FTO variants and the severity of MDD. 359 Lack of the FTO gene impacts anxiety-depression-like behavior in mice.”
BackgroundInfluential
- Authors
- Liu, S., Xiu, J., Zhu, C., Meng, K., Li, C., Han, R., Du, T., Li, L., Xu, L., Liu, R., Zhu, W., Shen, Y., & Xu, Q.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Xu, Qi
- Venue
- Nature Communications
- Published
- 2021-11-26
- Volume
- 12
- Issue
- 1
- Pages
- 6937-6937
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8626436
- OpenAlex
- W3216913785
- Cited by
- 118
- References
- 61
- Citations by year
- 2026: 22 · 2025: 29 · 2024: 23 · 2023: 29 · 2022: 15
- FWCI
- 5.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82101545, 20211, 2016YFC1306700, 2018B030334001, 81930104, 81625008, 31970952)
- Chinese Academy of Medical Sciences
- Peking Union Medical College
- National Key Research and Development Program of China (2016YFC1306700, 2020YFA0804502)
- Science and Technology Planning Project of Guangdong Province (2018B 030334001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- FTO, RNA demethylation, N6-methyladenosine, RNA methylation, major depressive disorder, depression-like behavior, hippocampus, epitranscriptomics, ADRB2, SIRT1, c-Myc, spine loss, post-transcriptional regulation
- MeSH terms
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Adenosine, Adult, Animals, Depressive Disorder, Major, Major Depressive Disorder, Disease Models, Animal, Female, Hippocampus, Humans, Male, Methylation, Middle Aged, Down-Regulation, Case-Control Studies, Receptors, Adrenergic, beta-2, Mice, Knockout, Mice, Gene Knockdown Techniques, Young Adult, Healthy Volunteers
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