Bidirectional Mendelian Randomization Indicates Causal Relationships Between Circulating Branched-Chain Amino Acids and Metabolic Health.

Branched-chain amino acids (BCAAs) are essential nutrients for humans. An elevated circulating BCAA level has been associated with obesity and type 2 diabetes (T2D), but the causal role of BCAAs 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, a higher circulating level of BCAAs seemed to be the outcome of poor metabolic health, including higher BMI, more circulating triglycerides (TGs), lower HDL cholesterol (HDL-C), greater insulin resistance, and higher T2D risk (all P < 6 × 10-4). Conversely, a higher level of BCAAs as the exposure seemed causally associated with more TGs and lower HDL-C (indicating dyslipidemia), independent of BMI and T2D risk. Our bioinformatic and functional analyses further identified PDE3B as a potential regulator of BCAAs and lipid metabolism in adipocytes. These findings confirm the role of circulating BCAAs as a biomarker reflecting metabolic health and identify a potential bidirectional causal link with lipid dysregulation. Additional studies should explore how BCAAs affect lipid metabolism in both insulin-resistant and metabolically healthy individuals. ARTICLE HIGHLIGHTS: We undertook this study to estimate the causal role of circulating branched-chain amino acids (BCAAs) in metabolic health using genetics. Are circulating BCAAs a cause or consequence of metabolic health? We found that a higher circulating level of BCAAs likely reflects poorer metabolic health. There is a potential bidirectional causal link between BCAAs and dyslipidemia that warrants further tissue-specific functional studies. Our findings suggest that BCAAs may causally affect lipid metabolism, with adipocytes as a key site. Understanding tissue-specific pathways of BCAA-induced lipid dysregulation could guide BCAAs' potential as a clinical intervention target.