| Title: | Bidirectional Mendelian Randomization Indicates Causal Relationships Between Circulating Branched-Chain Amino Acids and Metabolic Health |
| Journal: | Diabetes |
| Published: | 18 Jul 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40680056/ |
| DOI: | https://doi.org/10.2337/db24-1162 |
Publication 17007
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Abstract
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.</p>
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.</p>
13 Keywords
- Amino Acids, Branched-Chain
- Body Composition
- Body Mass Index
- Cholesterol, HDL
- Diabetes Mellitus, Type 2
- Female
- Humans
- Insulin Resistance
- Lipid Metabolism
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Triglycerides
11 Authors
- Raina Y. Jia
- Jian-Hua Chen
- Sam Lockhart
- Brian Y.H. Lam
- Katherine A. Kentistou
- Yajie Zhao
- Eugene J. Gardner
- John R.B. Perry
- Stephen O'Rahilly
- Felix R. Day
- Ken K. Ong
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