title: β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors.
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.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Roberts
authors.affiliation: 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.
authors.forename: Pontus
authors.initials: P
authors.lastname: Boström
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: O'Sullivan
authors.affiliation: 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.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Schinzel
authors.affiliation: 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.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewis
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Dejam
authors.affiliation: 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.
authors.forename: Youn-Kyoung
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Palma
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, 3 Blackfan Circle, CLS Building, Floor 11, Boston, MA 02115, USA.
authors.forename: Sondra
authors.initials: S
authors.lastname: Calhoun
authors.affiliation: Institutionen för Cell-Och Molekylärbiologi (CMB), Karolinska Institutet, von Eulers väg 3, 171 77 Stockholm, Sweden.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Georgiadi
authors.affiliation: 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.
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Vasan S
authors.initials: VS
authors.lastname: Ramachandran
authors.affiliation: 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.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.affiliation: Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors.forename: Claude
authors.initials: C
authors.lastname: Bouchard
authors.affiliation: Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Rankinen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Souza
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: 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.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Institut de Recherches Cliniques de Montreal, Montreal, QC H2W 1R7, Canada.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Estall
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Soukas
authors.affiliation: 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.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Cowan
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, 3 Blackfan Circle, CLS Building, Floor 11, Boston, MA 02115, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
authors.affiliation: 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: rgerszten@partners.org.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
mesh_terms: D052437:Adipocytes, Brown / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052438:Adipocytes, White / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000621:Aminoisobutyric Acids / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D015444:Exercise; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008659:Metabolic Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D010805:Physical Conditioning, Animal; D012307:Risk Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000621:Aminoisobutyric Acids; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C033435:3-aminoisobutyric acid