Hepatic Glucose Metabolism Disorder Induced by Adipose Tissue-Derived miR-548ag via DPP4 Upregulation.
Hepatic Glucose Metabolism Disorder Induced by Adipose Tissue-Derived miR-548ag via DPP4 Upregulation.
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DOI：
10.3390/ijms24032964
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发表时间：
2023-02-03
影响因子：
5.6
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中科院分区：
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本研究旨在探讨miR-548ag调控糖代谢的分子机制。我们首次发现miR-548ag在肥胖和2型糖尿病（T2DM）患者的腹部脂肪组织和血清中表达升高。有条件敲除脂肪组织Dicer可显著降低小鼠脂肪组织、血清和肝组织中miR-548ag的表达和含量。结合miRNA靶基因预测软件RNAseq和双荧光素酶报告基因检测，证实miR-548ag对DNMT3B和DPP4具有靶向调控作用。饮食诱导肥胖小鼠脂肪组织、血清和肝组织中miR-548ag和DPP4表达升高，DNMT3B表达降低。随后，体外和体内实验证实，脂肪组织来源的miR-548ag通过抑制DNMT3B和上调DPP4来损害糖耐量和胰岛素敏感性。此外，miR-548ag抑制剂显著改善了肥胖小鼠和db/db小鼠的不良代谢表型。这些结果揭示了肥胖受试者脂肪组织源性miR-548ag的表达增加，这可能通过靶向DNMT3B上调DPP4的表达，最终导致糖代谢紊乱。因此，miR-548ag可以作为治疗T2DM的潜在靶点。
The present study aimed to explore the molecular mechanism underlying the regulation of glucose metabolism by miR-548ag. For the first time, we found that miR-548ag expression was elevated in the abdominal adipose tissue and serum of subjects with obesity and type 2 diabetes mellitus (T2DM). The conditional knockout of adipose tissue Dicer notably reduced the expression and content of miR-548ag in mouse adipose tissue, serum, and liver tissue. The combined use of RNAseq, an miRNA target gene prediction software, and the dual luciferase reporter assay confirmed that miR-548ag exerts a targeted regulatory effect on DNMT3B and DPP4. miR-548ag and DPP4 expression was increased in the adipose tissue, serum, and liver tissue of diet-induced obese mice, while DNMT3B expression was decreased. It was subsequently confirmed both in vitro and in vivo that adipose tissue-derived miR-548ag impaired glucose tolerance and insulin sensitivity by inhibiting DNMT3B and upregulating DPP4. Moreover, miR-548ag inhibitors significantly improved the adverse metabolic phenotype in both obese mice and db/db mice. These results revealed that the expression of the adipose tissue-derived miR-548ag increased in obese subjects, and that this could upregulate the expression of DPP4 by targeting DNMT3B, ultimately leading to glucose metabolism disorder. Therefore, miR-548ag could be utilized as a potential target in the treatment of T2DM.