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<p>Endothelial cell (EC) dysfunction is a hallmark of obesity and Type 2 diabetes mellitus (T2DM), yet the mechanisms linking vascular stress to systemic metabolic diseases remain unclear. Here, we investigated the role of the mitochondrial protein FUN14 domain-containing 1 (FUNDC1) in EC under nutritional overload. Using high-fat diet (HFD)-fed EC-specific <i>Fundc1</i> knockout mice, human umbilical vein ECs, primary ECs, and vascular tissues from patients with obese/T2DM, we find that endothelial FUNDC1 expression is elevated under diabetic conditions, whereas its deletion protects mice from HFD-induced obesity, insulin resistance, and metabolic disorders. Mechanistically, overnutrition triggers nuclear export of the long isoform of SIRT3 (SIRT3-L) to mitochondria via FUNDC1, disinhibiting GATA2 and enhancing endothelin-1 (ET-1) production. Loss of FUNDC1 in ECs retains SIRT3-L in the nucleus, promoting GATA2 degradation and reducing ET-1. Endothelial FUNDC1 levels correlated positively with plasma ET-1 in individuals with obesity/T2DM. These findings identify endothelial FUNDC1 as a key regulator of vasculature-metabolic organ cross talks and obesity-diabetes transition.</p>

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Endothelial FUNDC1 regulates metabolic reprogramming and the obesity-diabetes transition through the SIRT3/GATA2/endothelin-1 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Jian Li,
  • Dayong Li,
  • Fujie Zhao,
  • Yadong Wang,
  • Hongmin Yao,
  • Yin Wu,
  • Junqing An,
  • Zhixue Liu,
  • Ye Ding,
  • Ming-Hui Zou

摘要

Endothelial cell (EC) dysfunction is a hallmark of obesity and Type 2 diabetes mellitus (T2DM), yet the mechanisms linking vascular stress to systemic metabolic diseases remain unclear. Here, we investigated the role of the mitochondrial protein FUN14 domain-containing 1 (FUNDC1) in EC under nutritional overload. Using high-fat diet (HFD)-fed EC-specific Fundc1 knockout mice, human umbilical vein ECs, primary ECs, and vascular tissues from patients with obese/T2DM, we find that endothelial FUNDC1 expression is elevated under diabetic conditions, whereas its deletion protects mice from HFD-induced obesity, insulin resistance, and metabolic disorders. Mechanistically, overnutrition triggers nuclear export of the long isoform of SIRT3 (SIRT3-L) to mitochondria via FUNDC1, disinhibiting GATA2 and enhancing endothelin-1 (ET-1) production. Loss of FUNDC1 in ECs retains SIRT3-L in the nucleus, promoting GATA2 degradation and reducing ET-1. Endothelial FUNDC1 levels correlated positively with plasma ET-1 in individuals with obesity/T2DM. These findings identify endothelial FUNDC1 as a key regulator of vasculature-metabolic organ cross talks and obesity-diabetes transition.