Bidirectional Mendelian randomization indicates causal relationships between circulating branched-chain amino acids and metabolic health

Branched-Chain Amino Acids (BCAA) are essential nutrients for humans. Elevated circulating BCAA has been previously associated with obesity and type 2 diabetes (T2D), but their causal role in metabolic health remains unclear. Using a two-sample bidirectional Mendelian randomization (MR) approach, we assessed the bidirectional causal effects of circulating BCAAs on body composition, lipids, glucose metabolism, and insulin sensitivity in ~250,000 UK Biobank participants. In MR models, higher circulating level of BCAA appears to be the outcome of poor metabolic health, including higher body mass index (BMI), higher circulating triglycerides (TG), lower HDL-C, higher insulin resistance and higher T2D risk (all P < 6×10⁻⁴). Conversely, a higher level of BCAA as the exposure appears causally associated with higher TG and lower HDL-C (indicating dyslipidaemia), independent of BMI and T2D risk. Our bioinformatic and functional analysis further identified PDE3B as a potential regulator of BCAA and lipid metabolism in adipocytes. These findings confirm the role of circulating BCAA as a biomarker reflecting metabolic health and identify a potential bidirectional causal link with lipid dysregulation. Further studies should explore how BCAAs affect lipid metabolism in both insulin-resistant and metabolically healthy individuals.