title: Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice.
abstract: Uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production. UCP1 is also found outside classical brown adipose tissue depots, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'. In humans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolically healthy phenotype, but whether a causal relationship exists is not clear. Here we report that human brite/beige adipocyte progenitors proliferate in response to pro-angiogenic factors, in association with expanding capillary networks. Adipocytes formed from these progenitors transform in response to adenylate cyclase activation from being UCP1 negative to being UCP1 positive, which is a defining feature of the beige/brite phenotype, while displaying uncoupled respiration. When implanted into normal chow-fed, or into high-fat diet (HFD)-fed, glucose-intolerant NOD-scid IL2rg(null) (NSG) mice, brite/beige adipocytes activated in vitro enhance systemic glucose tolerance. These adipocytes express neuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is strongly associated with human obesity. Pro-angiogenic conditions therefore drive the proliferation of human beige/brite adipocyte progenitors, and activated beige/brite adipocytes can affect systemic glucose homeostasis, potentially through a neuroendocrine mechanism.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: So Yun
authors.initials: SY
authors.lastname: Min
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Kady
authors.affiliation: Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Cardiovascular Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Minwoo
authors.initials: M
authors.lastname: Nam
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Raziel
authors.initials: R
authors.lastname: Rojas-Rodriguez
authors.affiliation: Clinical Translational Research Pathway, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Berkenwald
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jong Hun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Hye-Lim
authors.initials: HL
authors.lastname: Noh
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Cardiovascular Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Marcus P
authors.initials: MP
authors.lastname: Cooper
authors.affiliation: Cardiovascular Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Fitzgibbons
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brehm
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Silvia
authors.identifier: http://orcid.org/0000-0002-0009-4129
authors.initials: S
authors.lastname: Corvera
mesh_terms: D017667:Adipocytes / Q000378:metabolism* / Q000637:transplantation; D052437:Adipocytes, Brown / Q000378:metabolism / Q000637:transplantation; D052438:Adipocytes, White / Q000378:metabolism / Q000637:transplantation; D000328:Adult; D000368:Aged; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D002196:Capillaries; D017690:Cell Transplantation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D000067596:Interleukin-33 / Q000235:genetics / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009765:Obesity / Q000378:metabolism; D010101:Oxygen Consumption; D016133:Polymerase Chain Reaction; D045664:Proprotein Convertase 1 / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011506:Proteins; D012333:RNA, Messenger / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D051017:Apoptosis Regulatory Proteins; D001786:Blood Glucose; D004268:DNA-Binding Proteins; D004745:Enkephalins; D019012:Integrin beta1; D000067596:Interleukin-33; D007453:Iodide Peroxidase; D007473:Ion Channels; D024101:Mitochondrial Proteins; D045664:Proprotein Convertase 1; D011498:Protein Precursors; D011506:Proteins; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000071256:Uncoupling Protein 1; D000097564:Iodothyronine Deiodinase Type II; C502539:CIDEA protein, human; C506536:IL33 protein, human; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; C031017:ornithine decarboxylase antizyme; C029992:proenkephalin; C587576:PCSK1 protein, human