MYCT1-IFITM2/3 interaction links endothelial endolysosomal trafficking to white adipose tissue expansion

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• 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)

Vertebrates rely on a network of blood vessels to meet organ demands for oxygen and nutrients. While endothelial cells are known to transport excess nutrients to white adipose tissue (WAT) for energy storage, how their metabolic state impacts this process remains unclear. Here, we identify MYCT1 as a conserved, pan-endothelial protein essential for WAT expansion. Endothelial-specific MYCT1 deletion limited WAT expansion independently of angiogenesis, adipogenesis, or systemic metabolic parameters. Mechanistically, MYCT1 interacted with the transmembrane endolysosomal proteins IFITM2/3 to restrict nutrient consumption by the vascular barrier. Loss of MYCT1 caused IFITM2/3 accumulation in early endosomes, promoting excessive endolysosomal degradation and mTORC1 hyperactivation, limiting the WAT energy storage capacity. Notably, endothelial-specific mTORC1 activation through TSC1 deletion phenocopied the fat storage defects of MYCT1 deficiency. Our findings establish the MYCT1-IFITM2/3 complex as endothelial metabolic checkpoint regulating systemic energy storage. Targeting MYCT1-IFITM2/3 may offer new therapeutic options for obesity and metabolic disorders.

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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