β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-oxidation and is Inversely Correlated with Cardiometabolic Risk Factors

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2014 Jan 14

PMID 24411942

Citations 295

Authors

Lee D Roberts

Pontus Bostrom

John F OSullivan

Robert T Schinzel

Gregory D Lewis

Andre Dejam

Youn-Kyoung Lee

Melinda J Palma

Sondra Calhoun

Anastasia Georgiadi

Ming-Huei Chen

Vasan S Ramachandran

Martin G Larson

Claude Bouchard

Tuomo Rankinen

Amanda L Souza

Clary B Clish

Thomas J Wang

Jennifer L Estall

Alexander A Soukas

Chad A Cowan

Bruce M Spiegelman

Robert E Gerszten

Affiliations

Soon will be listed here.

Abstract

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.

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References

Bostrom P, Wu J, Jedrychowski M, Korde A, Ye L, Lo J . A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012; 481(7382):463-8. PMC: 3522098. DOI: 10.1038/nature10777. View

Schulz N, Himmelbauer H, Rath M, van Weeghel M, Houten S, Kulik W . Role of medium- and short-chain L-3-hydroxyacyl-CoA dehydrogenase in the regulation of body weight and thermogenesis. Endocrinology. 2011; 152(12):4641-51. PMC: 3359510. DOI: 10.1210/en.2011-1547. View

Chen M, Yang Q . GWAF: an R package for genome-wide association analyses with family data. Bioinformatics. 2009; 26(4):580-1. PMC: 2852219. DOI: 10.1093/bioinformatics/btp710. View

Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V . Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999; 98(1):115-24. DOI: 10.1016/S0092-8674(00)80611-X. View

Wright H, Clish C, Mikami T, Hauser S, Yanagi K, Hiramatsu R . A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J Biol Chem. 2000; 275(3):1873-7. DOI: 10.1074/jbc.275.3.1873. View

Gulick T, Cresci S, Caira T, Moore D, Kelly D . The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci U S A. 1994; 91(23):11012-6. PMC: 45156. DOI: 10.1073/pnas.91.23.11012. View

Petrovic N, Walden T, Shabalina I, Timmons J, Cannon B, Nedergaard J . Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown.... J Biol Chem. 2009; 285(10):7153-64. PMC: 2844165. DOI: 10.1074/jbc.M109.053942. View

Roberts L, Souza A, Gerszten R, Clish C . Targeted metabolomics. Curr Protoc Mol Biol. 2012; Chapter 30:Unit 30.2.1-24. PMC: 3334318. DOI: 10.1002/0471142727.mb3002s98. View

Shimomura Y, Honda T, Shiraki M, Murakami T, Sato J, Kobayashi H . Branched-chain amino acid catabolism in exercise and liver disease. J Nutr. 2005; 136(1 Suppl):250S-3S. DOI: 10.1093/jn/136.1.250S. View

10.

Xue B, Coulter A, Rim J, Koza R, Kozak L . Transcriptional synergy and the regulation of Ucp1 during brown adipocyte induction in white fat depots. Mol Cell Biol. 2005; 25(18):8311-22. PMC: 1234324. DOI: 10.1128/MCB.25.18.8311-8322.2005. View

11.

Guerra C, Koza R, Walsh K, Kurtz D, Wood P, Kozak L . Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation. J Clin Invest. 1998; 102(9):1724-31. PMC: 509120. DOI: 10.1172/JCI4532. View

12.

Xu X, Ying Z, Cai M, Xu Z, Li Y, Jiang S . Exercise ameliorates high-fat diet-induced metabolic and vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose tissue. Am J Physiol Regul Integr Comp Physiol. 2011; 300(5):R1115-25. PMC: 3094041. DOI: 10.1152/ajpregu.00806.2010. View

13.

Leskinen T, Rinnankoski-Tuikka R, Rintala M, Seppanen-Laakso T, Pollanen E, Alen M . Differences in muscle and adipose tissue gene expression and cardio-metabolic risk factors in the members of physical activity discordant twin pairs. PLoS One. 2010; 5(9). PMC: 2940764. DOI: 10.1371/journal.pone.0012609. View

14.

Suhre K, Wallaschofski H, Raffler J, Friedrich N, Haring R, Michael K . A genome-wide association study of metabolic traits in human urine. Nat Genet. 2011; 43(6):565-9. DOI: 10.1038/ng.837. View

15.

Lowell B, Hamann A, Lawitts J, Himms-Hagen J, Boyer B, Kozak L . Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature. 1993; 366(6457):740-2. DOI: 10.1038/366740a0. View

16.

Bouchard C, Leon A, Rao D, Skinner J, Wilmore J, Gagnon J . The HERITAGE family study. Aims, design, and measurement protocol. Med Sci Sports Exerc. 1995; 27(5):721-9. View

17.

Handschin C, Spiegelman B . Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev. 2006; 27(7):728-35. DOI: 10.1210/er.2006-0037. View

18.

Tiscornia G, Singer O, Verma I . Production and purification of lentiviral vectors. Nat Protoc. 2007; 1(1):241-5. DOI: 10.1038/nprot.2006.37. View

19.

Wu J, Bostrom P, Sparks L, Ye L, Choi J, Giang A . Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012; 150(2):366-76. PMC: 3402601. DOI: 10.1016/j.cell.2012.05.016. View

20.

Shimomura Y, Murakami T, Nakai N, Nagasaki M, Harris R . Exercise promotes BCAA catabolism: effects of BCAA supplementation on skeletal muscle during exercise. J Nutr. 2004; 134(6 Suppl):1583S-1587S. DOI: 10.1093/jn/134.6.1583S. View