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<p>Obesity impairs metabolic flexibility—the capacity to adapt to fluctuating energy demands. Emerging evidence suggests that dietary interventions, particularly time-restricted feeding (TRF), may help restore this flexibility. In this study, we demonstrate that feeding upregulates PRMT3 and asymmetric dimethylarginine (ADMA)-containing proteins via insulin–pAKT signaling, while fasting reduces their expression. Pharmacological inhibition of PRMT3 attenuates diet-induced obesity (DIO) and enhances adipocyte glycolysis in male mice. Mechanistically, PRMT3 drives the expression of citrate transporter SLC25A1 during feeding through direct arginine methylation. A 16:8 TRF regimen normalizes PRMT3 and ADMA levels while suppressing SLC25A1 expression. Notably, PRMT3 inhibition recapitulates the metabolic benefits of 16:8&#xa0;TRF and improves metabolic flexibility. Furthermore, adipocyte-specific deletion of <i>Slc25a1</i> in male mice protects against DIO and enhances insulin sensitivity. Collectively, these findings identify PRMT3-mediated arginine methylation in vWAT as a nutrient-responsive regulatory axis that impairs metabolic flexibility in obesity, which is a potential therapeutic target.</p>

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PRMT3-mediated post-translational adaptation to fasting regulates metabolic flexibility

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月2日

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  • Zhengyun Huang,
  • Xiangpeng Liu,
  • Xiyue Chen,
  • You Zhou,
  • Qian Chen,
  • Yan Liu,
  • Hongyun Zhu,
  • Ken Cheng,
  • Yu Feng,
  • Miren Dong,
  • Linsheng Song,
  • Lingling Wang,
  • Shiqi Liu,
  • Tizhong Shan,
  • Shihuan Kuang,
  • Yingying Dong,
  • Antonio Vidal-Puig,
  • Yong Zhang,
  • Zhihao Jia

摘要

Obesity impairs metabolic flexibility—the capacity to adapt to fluctuating energy demands. Emerging evidence suggests that dietary interventions, particularly time-restricted feeding (TRF), may help restore this flexibility. In this study, we demonstrate that feeding upregulates PRMT3 and asymmetric dimethylarginine (ADMA)-containing proteins via insulin–pAKT signaling, while fasting reduces their expression. Pharmacological inhibition of PRMT3 attenuates diet-induced obesity (DIO) and enhances adipocyte glycolysis in male mice. Mechanistically, PRMT3 drives the expression of citrate transporter SLC25A1 during feeding through direct arginine methylation. A 16:8 TRF regimen normalizes PRMT3 and ADMA levels while suppressing SLC25A1 expression. Notably, PRMT3 inhibition recapitulates the metabolic benefits of 16:8 TRF and improves metabolic flexibility. Furthermore, adipocyte-specific deletion of Slc25a1 in male mice protects against DIO and enhances insulin sensitivity. Collectively, these findings identify PRMT3-mediated arginine methylation in vWAT as a nutrient-responsive regulatory axis that impairs metabolic flexibility in obesity, which is a potential therapeutic target.