title: A Secreted Slit2 Fragment Regulates Adipose Tissue Thermogenesis and Metabolic Function.
abstract: Activation of brown and beige fat can reduce obesity and improve glucose homeostasis through nonshivering thermogenesis. Whether brown or beige fat also secretes paracrine or endocrine factors to promote and amplify adaptive thermogenesis is not fully explored. Here we identify Slit2, a 180 kDa member of the Slit extracellular protein family, as a PRDM16-regulated secreted factor from beige fat cells. In isolated cells and in mice, full-length Slit2 is cleaved to generate several smaller fragments, and we identify an active thermogenic moiety as the C-terminal fragment. This Slit2-C fragment of 50 kDa promotes adipose thermogenesis, augments energy expenditure, and improves glucose homeostasis in vivo. Mechanistically, Slit2 induces a robust activation of PKA signaling, which is required for its prothermogenic activity. Our findings establish a previously unknown peripheral role for Slit2 as a beige fat secreted factor that has therapeutic potential for the treatment of obesity and related metabolic disorders.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Katrin J
authors.initials: KJ
authors.lastname: Svensson
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Jedrychowski
authors.affiliation: Laboratory of Molecular Metabolism, Rockefeller University, New York, NY 10065, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Cohen
authors.affiliation: Metabolic Health Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Lo
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Serag
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Serkan
authors.initials: S
authors.lastname: Kir
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kosaku
authors.initials: K
authors.lastname: Shinoda
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Tartaglia
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Rao
authors.affiliation: Sorbonne Universités, UPMC Paris 06, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Chédotal
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kajimura
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: bruce_spiegelman@dfci.harvard.edu.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D000069797:Adipocytes, Beige / Q000378:metabolism; D052436:Adipose Tissue, White / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D015398:Signal Transduction; D022722:Thermogenesis; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D000098552:Slit Homolog 2 Protein