title: Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes.
abstract: Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. However, both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here we generated clones of brown and white preadipocytes from human neck fat and characterized their adipogenic and thermogenic differentiation. We combined an uncoupling protein 1 (UCP1) reporter system and expression profiling to define novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated. Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes using CRISPR-Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using the cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer potential biomarkers for identifying thermogenically competent preadipocytes.
authors.affiliation: 1] Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA. [2] Division of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Ruidan
authors.initials: R
authors.lastname: Xue
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lynes
authors.affiliation: 1] Bioinformatics Core, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Dreyfuss
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Farnaz
authors.initials: F
authors.lastname: Shamsi
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tim J
authors.identifier: 0000000284133972
authors.initials: TJ
authors.lastname: Schulz
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tian Lian
authors.initials: TL
authors.lastname: Huang
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Townsend
authors.affiliation: Division of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lauren S
authors.identifier: 0000000313801774
authors.initials: LS
authors.lastname: Weiner
authors.affiliation: Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: White
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Maureen S
authors.initials: MS
authors.lastname: Lynes
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.affiliation: Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Goodyear
authors.affiliation: 1] Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA. [2] Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Cypess
authors.affiliation: 1] Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA. [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Tseng
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology / Q000378:metabolism*; D052438:Adipocytes, White / Q000166:cytology / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D002999:Clone Cells; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D022722:Thermogenesis / Q000235:genetics*; D000071256:Uncoupling Protein 1
chemical_list: D015415:Biomarkers; C000588596:EDNRB protein, human; D020662:Guanine Nucleotide Exchange Factors; D019012:Integrin beta1; D007473:Ion Channels; D024101:Mitochondrial Proteins; C453280:PREX1 protein, human; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1