β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors

Lee D Roberts; Pontus Boström; John F O'Sullivan; 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

doi:10.1016/j.cmet.2013.12.003

β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors

Cell Metab. 2014 Jan 7;19(1):96-108. doi: 10.1016/j.cmet.2013.12.003.

Authors

Lee D Roberts¹, Pontus Boström², John F O'Sullivan¹, Robert T Schinzel³, Gregory D Lewis⁴, Andre Dejam¹, Youn-Kyoung Lee⁵, Melinda J Palma¹, Sondra Calhoun⁶, Anastasia Georgiadi⁷, Ming-Huei Chen⁸, Vasan S Ramachandran⁹, Martin G Larson¹⁰, Claude Bouchard¹¹, Tuomo Rankinen¹¹, Amanda L Souza¹², Clary B Clish¹², Thomas J Wang¹³, Jennifer L Estall¹⁴, Alexander A Soukas¹⁵, Chad A Cowan¹⁶, Bruce M Spiegelman⁶, Robert E Gerszten¹⁷

Affiliations

¹ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
² Dana-Farber Cancer Institute and Harvard Medical School, 3 Blackfan Circle, CLS Building, Floor 11, Boston, MA 02115, USA; Institutionen för Cell-Och Molekylärbiologi (CMB), Karolinska Institutet, von Eulers väg 3, 171 77 Stockholm, Sweden.
³ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Institut für Biologie-Mikrobiologie, Fachbereich Biologie, Chemie, Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 12-16,14195 Berlin, Germany.
⁴ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Dana-Farber Cancer Institute and Harvard Medical School, 3 Blackfan Circle, CLS Building, Floor 11, Boston, MA 02115, USA.
⁷ Institutionen för Cell-Och Molekylärbiologi (CMB), Karolinska Institutet, von Eulers väg 3, 171 77 Stockholm, Sweden.
⁸ Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University School of Medicine, Framingham, MA 01702, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
⁹ Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University School of Medicine, Framingham, MA 01702, USA; Cardiology Section, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, USA.
¹⁰ Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University School of Medicine, Framingham, MA 01702, USA; Department of Mathematics and Statistics, Boston University, Boston, MA 02215, USA.
¹¹ Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹³ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Cardiology Division, Vanderbilt University, Nashville, TN 37232, USA.
¹⁴ Institut de Recherches Cliniques de Montreal, Montreal, QC H2W 1R7, Canada.
¹⁵ Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹⁶ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹⁷ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: [email protected].

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.

Publication types

Clinical Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes, Brown / drug effects
Adipocytes, Brown / metabolism
Adipocytes, Brown / pathology
Adipocytes, White / drug effects
Adipocytes, White / metabolism
Adipocytes, White / pathology
Adipose Tissue, Brown / cytology
Adipose Tissue, Brown / drug effects
Adipose Tissue, Brown / metabolism*
Adipose Tissue, White / cytology
Adipose Tissue, White / drug effects
Adipose Tissue, White / metabolism*
Aminoisobutyric Acids / blood
Aminoisobutyric Acids / pharmacology*
Animals
Cardiovascular Diseases / metabolism*
Cardiovascular Diseases / pathology
Cell Differentiation / drug effects
Exercise
Gene Expression Regulation / drug effects
Glucose Tolerance Test
Humans
Induced Pluripotent Stem Cells / drug effects
Induced Pluripotent Stem Cells / metabolism
Liver / drug effects
Liver / metabolism*
Metabolic Diseases / metabolism*
Metabolic Diseases / pathology
Mice
Organ Specificity / drug effects
Organ Specificity / genetics
Oxidation-Reduction / drug effects
PPAR alpha / metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Phenotype
Physical Conditioning, Animal
Risk Factors
Transcription Factors / metabolism
Transcription, Genetic / drug effects
Weight Gain / drug effects

Substances

Aminoisobutyric Acids
PPAR alpha
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ppargc1a protein, mouse
Transcription Factors
3-aminoisobutyric acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding