ArticleNature medicine2016
A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance.
Article in Nature medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 375 papers, 2 of them syntheses that pooled it.
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Who cites it
375 citing papers in PubMed, 2 syntheses or guidelines pooled it, 567 citations in OpenAlex.
- Physical Activity and Metabolic Alterations in Children and Adolescents Across Different Weight Groups: A Systematic Review.European journal of sport science · 2026Pooled it
- Inappropriate Diet Exacerbates Metabolic Dysfunction-Associated Steatotic Liver Disease via Abdominal Obesity.Nutrients · 2024Pooled it
- A randomized placebo-controlled clinical trial for pharmacological activation of BCAA catabolism in patients with type 2 diabetes.Nature communications · 2022Trial
- Branched-chain amino acids and gut microbiota: coregulation and impact on neurological function via the gut-brain axis.Gut microbes · 2026Review
- High-protein diet promotes aging by activating the CG6415/AMT gene and disrupting mitochondrial homeostasis.Journal of advanced research · 2026Article
- The Role of Branched-Chain Amino Acids in Nutrient Allocation of the Porcine Placenta: A Review.Animals : an open access journal from MDPI · 2026Review
- Intermediate leucine catabolism is associated with longevity and sustained reproduction in grasshoppers.GeroScience · 2026Article
- Transcriptomic analysis of palmitoylation-related genes reveals a preferential association with BCAA catabolism in adipose tissue from pediatric obesity.Endocrine connections · 2026Article
- The emerging role of branched-chain amino acid metabolism in obesity.International journal of obesity (2005) · 2026Review
- BCKDK protects against obesity-induced cardiac remodelling and dysfunction by alleviating mitochondrial oxidative stress and ROS-driven MAPK signalling.Redox biology · 2026Article
- Endothelial Dysfunction and Metabolic Reprogramming in Cardiovascular Diseases.Reviews in cardiovascular medicine · 2026Review
- Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.Nature communications · 2026Article
- The hallmarks of protein and amino acid restriction in aging and longevity.Cell press blue · 2026Article
- Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.Nature aging · 2026Article
- Decoding the Gut-Fat-Heart Axis: From Molecular Communication Networks to Clinical Translation Strategies.International journal of molecular sciences · 2026Review
- The significance of the ketolytic gene OXCT1 in metabolism, intracellular signaling and disease development.Cellular and molecular life sciences : CMLS · 2026Review
- Cardiac Lipid Metabolism: Cells, Metabolites, and Rhythms.Circulation research · 2026Review
- The Triangular Interaction Between Dietary Polyphenols, Gut Microbiota and Type 2 Diabetes.International journal of molecular sciences · 2026Review
- Association of metabolic vulnerability index with various chronic liver diseases and mortality: a large prospective cohort study.BMC gastroenterology · 2026Article
- ACAD8 deficiency promotes pathological cardiac hypertrophy in response to pressure overload by regulating histone isobutyrylation.Nature communications · 2026Article
315 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 5 institutions in 1 country.
Funding
Abstract
Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1α; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1α to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.