Metformin combats obesity by targeting FTO in an m<sup>6</sup>A-YTHDF2-dependent manner

Liao, Xing; Liu, Jiaqi; Chen, Yushi; Liu, Youhua; Chen, Wei; Zeng, Botao; Liu, Yuxi; Luo, Yaojun; Huang, Chaoqun; Guo, Gaochao; Wang, Yizhen; Wang, Xinxia

doi:10.1080/1061186x.2022.2071906

Cited by 13 publications

(5 citation statements)

References 45 publications

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“…Loss of FTO significantly decreased the expression of cyclin A2 (CCNA2) and cyclin-dependent kinase 2 (CDK2) mRNA by increasing their m 6 A levels, thereby delaying cell cycle progression and inhibiting adipogenesis in 3T3-L1 cells [24]. Metformin increases m 6 A methylation levels of CCND1 and CDK2 by inhibiting FTO expression, thereby inhibiting adipogenesis and combating obesity [25]. In our study, overexpression and knockdown of FTO markedly altered the mRNA and protein expression levels of CTNNB1 in an m 6 A modification manner.…”

Section: Discussionmentioning

confidence: 99%

“…He Chuan's team first found that the knockout of FTO in human cells led to an increase in the global m 6 A level of mRNA [22]. FTO was found to regulate rodent adipogenesis by affecting alternative splicing of mRNA [23], RNA stability [24], and degradation [25] in an m 6 A-dependent manner. However, the regulatory role of FTO on chicken adipogenesis remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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m6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte

Huang

Wang

et al. 2022

J Animal Sci Biotechnol

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Background N6-methyladenosine (m6A) is an abundant post-transcriptional RNA modification that affects various biological processes. The fat mass and obesity-associated (FTO) protein, a demethylase encoded by the FTO gene, has been found to regulate adipocyte development in an m6A-dependent manner in multiple species. However, the effects of the m6A methylation and FTO demethylation functions on chicken adipogenesis remain unclear. This study aims to explore the association between m6A modification and chicken adipogenesis and the underlying mechanism by which FTO affects chicken preadipocyte development. Results The association between m6A modification and chicken lipogenesis was assessed by treating chicken preadipocytes with different doses of methyl donor betaine and methylation inhibitor cycloleucine. The results showed that betaine significantly increased methylation levels and inhibited lipogenesis, and the inverse effect was found in preadipocytes after cycloleucine treatment. Overexpression of FTO significantly inhibited m6A levels and promoted proliferation and differentiation of chicken preadipocytes. Silencing FTO showed opposite results. Mechanistically, FTO overexpression increased the expression of catenin beta 1 (CTNNB1) by improving RNA stability in an m6A-dependent manner, and we proved that FTO could directly target CTNNB1. Furthermore, CTNNB1 may be a positive regulator of adipogenesis in chicken preadipocytes. Conclusions m6A methylation of RNA was negatively associated with adipogenesis of chicken preadipocytes. FTO could regulate CTNNB1 expression in a demethylation manner to promote lipogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

m6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte

Huang

Wang

et al. 2022

J Animal Sci Biotechnol

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“…Cell cycle factors, including CCNA2, CDK2, and CCND1 promote cell cycle progression and mitotic clonal expression in adipocytes ( 94 , 95 ). Epigallocatechin gallate (EGCG) and metformin reduce CCNA2 and CDK2 levels by increasing m 6 A modification in an FTO-YTHDF2-dependent manner ( 96 , 97 ). Conversely, Zinc finger protein (Zfp217) binds and sequesters YTHDF2 to reduce m 6 A levels, thus reversing CCND1 mRNA degradation ( 98 ).…”

Section: The Roles Of the Ythdf Family In Physiological And Pathologi...mentioning

confidence: 99%

N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms

Chen

Gao

et al. 2023

Front. Immunol.

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As the most abundant and conserved internal modification in eukaryote RNAs, N6-methyladenosine (m6A) is involved in a wide range of physiological and pathological processes. The YT521-B homology (YTH) domain-containing family proteins (YTHDFs), including YTHDF1, YTHDF2, and YTHDF3, are a class of cytoplasmic m6A-binding proteins defined by the vertebrate YTH domain, and exert extensive functions in regulating RNA destiny. Distinct expression patterns of the YTHDF family in specific cell types or developmental stages result in prominent differences in multiple biological processes, such as embryonic development, stem cell fate, fat metabolism, neuromodulation, cardiovascular effect, infection, immunity, and tumorigenesis. The YTHDF family mediates tumor proliferation, metastasis, metabolism, drug resistance, and immunity, and possesses the potential of predictive and therapeutic biomarkers. Here, we mainly summary the structures, roles, and mechanisms of the YTHDF family in physiological and pathological processes, especially in multiple cancers, as well as their current limitations and future considerations. This will provide novel angles for deciphering m6A regulation in a biological system.

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“…Thus, it is the first-line drug for T2D recommended in the latest American Diabetes Association and European Association for the Study of Diabetes consensus (119,120). A recent study showed (121) that metformin affects adipogenesis by altering adipose tissue m6A modification to decrease fat mass and alleviate IR in vivo. In the in vitro experiment, metformin-treated 3T3-L1 cells showed an increased G0/G1 phase ratio and a decreased ratio of S and G2/M phases.…”

Section: The M6a Modification and Clinical Applicationmentioning

confidence: 99%

N6-methyladenosine RNA modification: an emerging molecule in type 2 diabetes metabolism

Zhang

Gang

et al. 2023

Front. Endocrinol.

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Type 2 diabetes (T2D) is a metabolic disease with an increasing rate of incidence worldwide. Despite the considerable progress in the prevention and intervention, T2D and its complications cannot be reversed easily after diagnosis, thereby necessitating an in-depth investigation of the pathophysiology. In recent years, the role of epigenetics has been increasingly demonstrated in the disease, of which N6-methyladenosine (m6A) is one of the most common post-transcriptional modifications. Interestingly, patients with T2D show a low m6A abundance. Thus, a comprehensive analysis and understanding of this phenomenon would improve our understanding of the pathophysiology, as well as the search for new biomarkers and therapeutic approaches for T2D. In this review, we systematically introduced the metabolic roles of m6A modification in organs, the metabolic signaling pathways involved, and the effects of clinical drugs on T2D.

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Metformin combats obesity by targeting FTO in an m⁶A-YTHDF2-dependent manner

Cited by 13 publications

References 45 publications

m6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte

m6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte

N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms

N6-methyladenosine RNA modification: an emerging molecule in type 2 diabetes metabolism

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Metformin combats obesity by targeting FTO in an m6A-YTHDF2-dependent manner

Cited by 13 publications

References 45 publications

m6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte

m6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte

N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms

N6-methyladenosine RNA modification: an emerging molecule in type 2 diabetes metabolism

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Metformin combats obesity by targeting FTO in an m⁶A-YTHDF2-dependent manner