Muscle-Liver Trafficking of BCAA-Derived Nitrogen Underlies Obesity-Related Glycine Depletion.

Glycine levels are inversely associated with branched-chain amino acids (BCAAs) and cardiometabolic disease phenotypes, but biochemical mechanisms that explain these relationships remain uncharted. Metabolites and genes related to BCAA metabolism and nitrogen handling were strongly associated with glycine in correlation analyses. Stable isotope labeling in Zucker fatty rats (ZFRs) shows that glycine acts as a carbon donor for the pyruvate-alanine cycle in a BCAA-regulated manner. Inhibition of the BCAA transaminase (BCAT) enzymes depletes plasma pools of alanine and raises glycine levels. In high-fat-fed ZFRs, dietary glycine supplementation raises urinary acyl-glycine content and lowers circulating triglycerides but also results in accumulation of long-chain acyl-coenzyme As (acyl-CoAs), lower 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in muscle, and no improvement in glucose tolerance. Collectively, these studies frame a mechanism for explaining obesity-related glycine depletion and also provide insight into the impact of glycine supplementation on systemic glucose, lipid, and amino acid metabolism.

Duke Scholars

Author William Erle Kraus Medicine, Cardiology

Author Phillip James White Medicine, Endocrinology, Metabolism, and Nutrition

Author Robert W. McGarrah III Medicine, Cardiology

Author Olga Ilkayeva Medicine, Endocrinology, Metabolism, and Nutrition

Author James R. Bain Medicine, Endocrinology, Metabolism, and Nutrition

Author Timothy Robert Koves Medicine, Geriatrics

Author Deborah Marie Muoio Medicine, Endocrinology, Metabolism, and Nutrition

Author Svati Hasmukh Shah Medicine, Cardiology

Author Christopher Bang Newgard Pharmacology & Cancer Biology