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

Early human evidence such as case series or small samples is exploring possible benefits.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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.

Evidence level

Early human evidence such as case series or small samples is exploring possible benefits.

Browse all related research

Filter the research library by this study's title keywords, author, or publication year.