The emerging role of branched-chain amino acid metabolism in obesity.

Abstract

Obesity is a chronic and complex disease defined by excessive deposits of fat that may lead to health damage. Branched-chain amino acids (BCAAs), including valine, leucine, and isoleucine, play a significant role in obesity and metabolic processes. BCAA metabolic disorders are a core feature of obesity and its associated metabolic syndrome, but the specific mechanisms and clinical significance remain highly controversial. This review aims to deeply explore the multifaceted roles of BCAAs in obesity. We first outline the catabolic pathways of BCAAs, summarize the key roles of branched-chain α-keto acids (BCKAs) and 3-hydroxyisobutyric acid (3-HIB) as metabolic intermediates in mediating insulin signaling dysregulation, and analyze how BCAA metabolic disorders drive the progression of obesity and its complications by impairing insulin sensitivity, disrupting lipid homeostasis, and exacerbating chronic inflammation. Additionally, to reconcile the long-standing controversy over whether BCAAs are beneficial or harmful, this review provides new insights. Finally, we summarize potential strategies for targeting BCAA metabolism through dietary modifications, exercise interventions, and drug therapies. This review aims to deepen the understanding of the complex role of BCAAs in obesity and lay a theoretical foundation for precise prevention and strategies targeting metabolic pathway imbalances. BCAAs regulate obesity through pathways that affect insulin sensitivity, lipid metabolism, and inflammatory. Insulin sensitivity is regulated by the activity of the mTORC1 signaling pathway and the functional state of mitochondria. The metabolism of branched-chain amino acids influences lipid synthesis and breakdown by inhibiting BCAT2. Elevated levels of branched-chain amino acids may exacerbate inflammatory through macrophage infiltration and the secretion of pro-inflammatory cytokines. On the right are different intervention measures for regulating BCAA levels, including dietary, exercise and drug interventions. (Note:The symbol "↑" indicates promotion/increase, and "↓" indicates inhibition/decrease.).