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METTL14-Induced M6A Methylation Increases G6pc Biosynthesis, Hepatic Glucose Production and Metabolic Disorders in

Qiantao Zheng1,2, Xiao Zhong1,3, Qianqian Kang1,2

  • 1Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 25, 2025
PubMed

Insights

METTL14 regulates glucose metabolism by controlling N6-methyladenosine (m6A) levels on Glucose-6-phosphatase catalytic subunit (G6pc) mRNA. This finding reveals a new axis impacting hepatic glucose production in metabolic disease.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Metabolism

Background:

  • N6-methyladenosine (m6A) modification of mRNA regulates gene expression, impacting various cellular processes.
  • Hepatic glucose production (HGP) is critical for glucose homeostasis, but its regulation, particularly by posttranscriptional mechanisms like m6A, is not fully understood.
  • Glucose-6-phosphatase catalytic subunit (G6pc) is a key enzyme in HGP, yet its precise regulatory network remains incomplete.

Purpose of the Study:

  • To investigate the role of METTL14 as a posttranscriptional regulator of G6pc in liver metabolism.
  • To elucidate the mechanism by which METTL14 influences G6pc mRNA stability, translation, and subsequent hepatic glucose production.
  • To explore the implications of the METTL14-G6pc axis in diet-induced obesity and metabolic disease.

Main Methods:

  • Utilized mouse models with diet-induced obesity to examine METTL14 and G6pc expression.
  • Employed in vitro and in vivo experiments to assess the impact of METTL14 manipulation on G6pc mRNA m6A modification, stability, and translation.
  • Identified m6A sites on G6pc mRNA and investigated the binding of m6A readers (YTHDF1, YTHDF3) to m6A-modified G6pc mRNA.
  • Assessed gluconeogenesis and HGP in hepatocytes, liver slices, and mice with altered Mettl14 expression.

Main Results:

  • METTL14, METTL3, and m6A-modified G6pc mRNA were upregulated in obese mice.
  • METTL14 deletion decreased G6pc mRNA m6A, while overexpression increased it; specific m6A sites were identified and critical for methylation.
  • METTL14 enhanced G6pc mRNA stability and translation, promoting G6pc biosynthesis, an effect dependent on m6A sites.
  • YTHDF1 and YTHDF3 readers bound to m6A-G6pc mRNA, facilitating G6pc synthesis.
  • Mettl14 deficiency impaired gluconeogenesis and HGP, which was rescued by hepatocyte-specific G6pc restoration.

Conclusions:

  • METTL14 acts as a key posttranscriptional regulator of G6pc mRNA, influencing its m6A modification, stability, and translation.
  • The METTL14-G6pc mRNA m6A axis plays a crucial role in regulating hepatic glucose production and biosynthesis.
  • This pathway represents a potential therapeutic target for managing metabolic diseases characterized by dysregulated glucose metabolism.
Keywords:
G6pcYTHDF1YTHDF3gluconeogenesishepatic glucose productionm6A, METTL14obesitytype 2 diabetes

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