title: Overexpressing the novel autocrine/endocrine adipokine WISP2 induces hyperplasia of the heart, white and brown adipose tissues and prevents insulin resistance.
abstract: WISP2 is a novel adipokine, most highly expressed in the adipose tissue and primarily in undifferentiated mesenchymal cells. As a secreted protein, it is an autocrine/paracrine activator of canonical WNT signaling and, as an intracellular protein, it helps to maintain precursor cells undifferentiated. To examine effects of increased WISP2 in vivo, we generated an aP2-WISP2 transgenic (Tg) mouse. These mice had increased serum levels of WISP2, increased lean body mass and whole body energy expenditure, hyperplastic brown/white adipose tissues and larger hyperplastic hearts. Obese Tg mice remained insulin sensitive, had increased glucose uptake by adipose cells and skeletal muscle in vivo and ex vivo, increased GLUT4, increased ChREBP and markers of adipose tissue lipogenesis. Serum levels of the novel fatty acid esters of hydroxy fatty acids (FAHFAs) were increased and transplantation of Tg adipose tissue improved glucose tolerance in recipient mice supporting a role of secreted FAHFAs. The growth-promoting effect of WISP2 was shown by increased BrdU incorporation in vivo and Tg serum increased mesenchymal precursor cell proliferation in vitro. In contrast to conventional canonical WNT ligands, WISP2 expression was inhibited by BMP4 thereby allowing normal induction of adipogenesis. WISP2 is a novel secreted regulator of mesenchymal tissue cellularity.
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: John R
authors.initials: JR
authors.lastname: Grünberg
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Hoffmann
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Shahram
authors.initials: S
authors.lastname: Hedjazifar
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Nerstedt
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lachmi
authors.initials: L
authors.lastname: Jenndahl
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Johannes
authors.initials: J
authors.lastname: Elvin
authors.affiliation: Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: John
authors.initials: J
authors.lastname: Castellot
authors.affiliation: Massachussetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Wei
authors.affiliation: Centre for Bone and Arthritis Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Movérare-Skrtic
authors.affiliation: Centre for Bone and Arthritis Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: The Wallenberg Laboratory, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Louise Mannerås
authors.initials: LM
authors.lastname: Holm
authors.affiliation: The Wallenberg Laboratory, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.|Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.affiliation: Department of Medicine, Beth Israel Deaconess and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ismail
authors.initials: I
authors.lastname: Syed
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
authors.affiliation: Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.affiliation: Department of Medicine, Beth Israel Deaconess and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Hammarstedt
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D015415:Biomarkers; D001823:Body Composition; D001835:Body Weight; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size; D004734:Energy Metabolism; D015870:Gene Expression; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006965:Hyperplasia; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D050155:Lipogenesis / Q000235:genetics; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015415:Biomarkers; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D051275:Glucose Transporter Type 4; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; C539089:WISP-2 protein, mouse; D005947:Glucose