title: Genetic and functional characterization of clonally derived adult human brown adipocytes.
abstract: Brown adipose tissue (BAT) acts in mammals as a natural defense system against hypothermia, and its activation to a state of increased energy expenditure is believed to protect against the development of obesity. Even though the existence of BAT in adult humans has been widely appreciated, its cellular origin and molecular identity remain elusive largely because of high cellular heterogeneity within various adipose tissue depots. To understand the nature of adult human brown adipocytes at single cell resolution, we isolated clonally derived adipocytes from stromal vascular fractions of adult human BAT from two individuals and globally analyzed their molecular signatures. We used RNA sequencing followed by unbiased genome-wide expression analyses and found that a population of uncoupling protein 1 (UCP1)-positive human adipocytes possessed molecular signatures resembling those of a recruitable form of thermogenic adipocytes (that is, beige adipocytes). In addition, we identified molecular markers that were highly enriched in UCP1-positive human adipocytes, a set that included potassium channel K3 (KCNK3) and mitochondrial tumor suppressor 1 (MTUS1). Further, we functionally characterized these two markers using a loss-of-function approach and found that KCNK3 and MTUS1 were required for beige adipocyte differentiation and thermogenic function. The results of this study present new opportunities for human BAT research, such as facilitating cell-based disease modeling and unbiased screens for thermogenic regulators.
authors.affiliation: 1] Diabetes Center, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA.
authors.forename: Kosaku
authors.initials: K
authors.lastname: Shinoda
authors.affiliation: 1] Diabetes Center, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA. [4] Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Ineke H N
authors.initials: IH
authors.lastname: Luijten
authors.affiliation: 1] Diabetes Center, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: 1] Diabetes Center, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA.
authors.forename: Haemin
authors.initials: H
authors.lastname: Hong
authors.affiliation: 1] Diabetes Center, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA.
authors.forename: Si B
authors.initials: SB
authors.lastname: Sonne
authors.affiliation: 1] Diabetes Center, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA.
authors.forename: Miae
authors.initials: M
authors.lastname: Kim
authors.affiliation: 1] Joslin Diabetes Center, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ruidan
authors.initials: R
authors.lastname: Xue
authors.affiliation: 1] Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas, USA. [2] Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA. [3] Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA. [4] Department of Nutrition and Metabolism, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Chondronikola
authors.affiliation: 1] Joslin Diabetes Center, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Cypess
authors.affiliation: 1] Joslin Diabetes Center, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Tseng
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Nedergaard
authors.affiliation: 1] Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas, USA. [2] Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA. [3] Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA. [4] Department of Nutrition and Metabolism, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Labros S
authors.initials: LS
authors.lastname: Sidossis
authors.affiliation: 1] Diabetes Center, University of California, San Francisco (UCSF), San Francisco, California, USA. [2] Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA. [3] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kajimura
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology*; D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics*; D034622:RNA Interference; D022722:Thermogenesis / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000071256:Uncoupling Protein 1
chemical_list: D002352:Carrier Proteins; D007473:Ion Channels; C474762:MTUS1 protein, human; D024101:Mitochondrial Proteins; C488664:Mtus1 protein, mouse; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; D025521:Tumor Suppressor Proteins; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C420132:potassium channel subfamily K member 3