IDH3A Deficiency Compromises Adaptive Thermogenesis and Exacerbates Obesity-Induced Metabolic Dysfunction via Impaired BCKDHA-Dependent BCAA Catabolism

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)

Adaptive thermogenesis in beige adipocytes is essential for maintaining energy homeostasis and preventing obesity. Emerging evidence suggests that human visceral adipose tissue harbors adipocytes with beige-like thermogenic features, enabling analysis of thermogenic gene regulation in humans. Isocitrate dehydrogenase 3A (IDH3A) is a rate-limiting enzyme of the tricarboxylic acid cycle, yet its function in adipocytes remains poorly defined. In this study, we examined IDH3A expression in human visceral adipose tissue and generated adipocyte-specific IDH3A knockout mice to investigate its role in beige adipocyte thermogenesis and metabolic regulation. IDH3A expression in human visceral fat was inversely associated with adiposity and adverse metabolic traits. Moreover, IDH3A expression was induced in human and mouse adipocytes following thermogenic stimulation. Adipocyte-specific IDH3A deletion in mice impaired beige fat thermogenic capacity, led to cold intolerance, and exacerbated diet-induced metabolic dysfunction. Mechanistically, IDH3A deficiency increased DNA methylation at the Bckdha promoter, resulting in the repression of this key branched-chain amino acid (BCAA) catabolic gene and impaired BCAA catabolism. Notably, restoring BCKDHA in IDH3A-deficient adipocytes rescued respiration and thermogenic function. Together, in addition to its canonical enzymatic role, our finding

Evidence level

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

Browse all related research

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