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

被引：59

作者：

White, Phillip J. ^{[1
,2
,3
]}

Lapworth, Amanda L. ^{[4
]}

McGarrah, Robert W. ^{[1
,5
]}

Kwee, Lydia Coulter ^{[1
]}

Crown, Scott B. ^{[1
]}

Ilkayeva, Olga ^{[1
,3
]}

An, Jie ^{[1
]}

Carson, Matthew W. ^{[6
]}

Christopher, Bridgette A. ^{[1
,5
]}

Ball, James R. ^{[1
]}

Davies, Michael N. ^{[1
]}

Kjalarsdottir, Lilja ^{[1
]}

George, Tabitha ^{[1
]}

Muehlbauer, Michael J. ^{[1
]}

Bain, James R. ^{[1
,3
]}

Stevens, Robert D. ^{[1
,3
]}

Koves, Timothy R. ^{[1
,7
]}

Muoio, Deborah M. ^{[1
,2
,3
]}

Brozinick, Joseph T. ^{[6
]}

Gimeno, Ruth E. ^{[6
]}

Brosnan, M. Julia ^{[4
]}

Rolph, Timothy P. ^{[4
]}

Kraus, William E. ^{[1
,5
]}

Shah, Svati H. ^{[1
,5
]}

Newgard, Christopher B. ^{[1
,2
,3
]}

机构：

[1] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Duke Mol Physiol Inst, Durham, NC 27708 USA

[2] Duke Univ, Dept Pharmacol, Med Ctr, Durham, NC 27708 USA

[3] Duke Univ, Med Ctr, Dept Med, Div Endocrinol, Durham, NC 27710 USA

[4] Pfizer, CV & Metab Dis Res Unit, Cambridge, MA USA

[5] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA

[6] Lilly Corp Ctr, Div Eli Lilly & Co, Lilly Res Labs, Diabet Therapeut Area, Indianapolis, IN USA

[7] Duke Univ, Med Ctr, Dept Med, Div Geriatr, Durham, NC 27710 USA

来源：

CELL REPORTS | 2020年 / 33卷 / 06期

关键词：

amino acids; metabolism; obesity; skeletal muscle;

D O I：

10.1016/j.celrep.2020.108375

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：17

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