The role of RNA m<sup>6</sup>A methylation in insulin resistance in adipocytes

Ye Diwen; Zhang Bingyang; Zhang Dantong; Ma Wanshan; Lu Sumei

doi:10.13406/j.cnki.cyxb.003432

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The role of RNA m⁶A methylation in insulin resistance in adipocytes

Basic research | 更新时间：2025-10-22

- The role of RNA m⁶A methylation in insulin resistance in adipocytes
- Journal of Chongqing Medical University Vol. 49, Issue 2, Pages: 132-140(2024)
- 作者机构：
  
  1.潍坊医学院医学检验学院，潍坊　261000
  2.山东大学齐鲁医学院，济南　250000
  3.山东第一医科大学第一附属医院/ 山东省千佛山医院检验医学，山东省医药卫生临床检验诊断学重点实验室，济南　250000
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003432
  CLC： R34
- Received：26 September 2023，
  
  Revised：2023-12-13，
  
  Accepted：15 December 2023，
  
  Published：28 February 2024
- 稿件说明：
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叶棣文,张炳杨,张丹彤,等.RNA m⁶A甲基化修饰在脂肪细胞胰岛素抵抗中的作用机制[J].重庆医科大学学报,2024,49(2):132-140.

Ye Diwen,Zhang Bingyang,Zhang Dantong,et al.The role of RNA m⁶A methylation in insulin resistance in adipocytes[J].Journal of Chongqing Medical University,2024,49(2):132-140.
叶棣文,张炳杨,张丹彤,等.RNA m⁶A甲基化修饰在脂肪细胞胰岛素抵抗中的作用机制[J].重庆医科大学学报,2024,49(2):132-140. DOI： 10.13406/j.cnki.cyxb.003432.

Ye Diwen,Zhang Bingyang,Zhang Dantong,et al.The role of RNA m⁶A methylation in insulin resistance in adipocytes[J].Journal of Chongqing Medical University,2024,49(2):132-140. DOI： 10.13406/j.cnki.cyxb.003432.

摘要

目的

探讨RNA m

A甲基化修饰在脂肪细胞胰岛素抵抗中的

作用及机制。

方法

收集2型糖尿病患者术中赘余皮下脂肪组织，以非2型糖尿病患者同样组织为对照，检测组间RNA m

A水平。高脂饮食诱导C57BL/6J小鼠构建胰岛素抵抗（insulin resistance，IR）模型（HFD组，

=5，60%高脂饲料喂养16周），对照组10%低脂饲料喂养16周（CD组，

=5）。模型构建成功后，取附睾周围脂肪组织行表观转录组学m

A甲基化修饰芯片检测，并借助MeRIP-qPCR实验、RT-qPCR以及RNA结合蛋白免疫沉淀测定（RNA Binding Protein Immunoprecipitation Assay，RIP）实验验证胰岛素信号转导相关基因变化；进一步观察METTL3小分子抑制剂STM2457对高脂饮食诱导下小鼠胰岛素信号转导基因的影响。

结果

2型糖尿病患者和小鼠IR模型脂肪组织中总体m

A修饰水平均升高（患者200 ng RNA

=-8.375，

0.001；患者100 ng RNA

=-3.722，

=0.006；患者50 ng RNA

=-4.937；

=0.001；小鼠100 ng RNA

=-3.590，

=0.023；小鼠50 ng RNA

=-2.760，

=0.025）。表观转录组学检测证实IR的脂肪组织中1 175个基因发生高m

A修饰，55个基因发生低m

A修饰，同时有182个基因呈现高m

A修饰且低表达，包括

AKT2、INSR、PIK3R1、ACACA、SREBF1

等5个胰岛素信号转导关键基因，其中

AKT2、INSR、ACACA、SREBF1

等4个基因被确证并证实其与METTL3存在直接结合，其m

A修饰水平受METTL3正向调控。STM2457作用下，胰岛素敏感性提高，且

AKT2、INSR、ACACA、SREBF1

转录水平上调，提示IR表型改善明显。

结论

高脂饮食通过METTL3诱导脂肪细胞胰岛素信号转导基因

AKT2、INSR、ACACA、SREBF1

发生m

A高甲基化修饰，诱导其低表达，阻滞胰岛素信号转导，进而参与诱发IR。

Abstract

Objective

To explore the role of RNA m

A methylation in insulin resistance in adipocytes.

Methods

We collected redundant subcutaneous adipose tissue samples from patients with type 2 diabetes and patients without type 2 diabetes to measure the RNA m

A modification level. A insulin resistance（IR） model was established by feeding C57BL/6J mice with a 60% high-fat diet for 16 weeks（

=5），while the control group was fed with a 10% low-fat diet for 16 weeks（

=5）. After successful modeling，the adipose tissue around the epididymis was

taken to detect m

A methylation using epitranscriptomic microarrays. The changes in insulin signaling-related genes were determined by MeRIP-qPCR assay，RT-qPCR，and RIP assay. The effects of the small-molecule inhibitor STM2457 targeting methyltransferase like 3（METTL3） on insulin signaling-related genes in mice feeding a high-fat diet were investigated.

Results

The overall m

A modification levels were significantly increased in the adipose tissue of patients with type 2 diabetes and IR mice（patients 200 ng RNA，

=-8.375，

0.001；patients 100 ng RNA，

=-3.722，

=0.006；patients 50 ng RNA，

=-4.937，

=0.001；mice 100 ng RNA，

=-3.590，

=0.023；mice 50 ng RNA，

=-2.760，

=0.025）. The epitranscriptomic assay detected high m

A methylation levels in 1 175 genes and low m

A methylation levels in 55 genes；182 genes showed significantly high m

A modification and low expression，including five key insulin signaling-related genes（

AKT2

，

INSR

，

PIK3R1

，

ACACA

，and

SREBF1

）. Direct binding between

AKT2

，

INSR

，

ACACA

，and

SREBF1

and METTL3 was validated，and their m

A modification levels were positively regulated by METTL3. STM2457 significantly increased insulin sensitivity，and significantly upregulated the transcriptional levels of

AKT2

，

INSR

，

ACACA

，and

SREBF1

，suggesting a significant improvement in IR phenotype.

Conclusion

High-fat diet induces IR through METTL3，which mediates m

A hypermethylation of

AKT2

，

INSR

，

ACACA

，and

SREBF1

to downregulate their expression an

d block insulin signaling in adipocytes.

关键词

Keywords

references

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⁰

The role of RNA m6A methylation in insulin resistance in adipocytes

DOI：10.13406/j.cnki.cyxb.003432

摘要

Abstract

关键词

Keywords

references

The role of RNA m⁶A methylation in insulin resistance in adipocytes