title: BMP4 and BMP Antagonists Regulate Human White and Beige Adipogenesis.
abstract: The limited expandability of subcutaneous adipose tissue, due to reduced ability to recruit and differentiate new adipocytes, prevents its buffering effect in obesity and is characterized by expanded adipocytes (hypertrophic obesity). Bone morphogenetic protein-4 (BMP4) plays a key role in regulating adipogenic precursor cell commitment and differentiation. We found BMP4 to be induced and secreted by differentiated (pre)adipocytes, and BMP4 was increased in large adipose cells. However, the precursor cells exhibited a resistance to BMP4 owing to increased secretion of the BMP inhibitor Gremlin-1 (GREM1). GREM1 is secreted by (pre)adipocytes and is an inhibitor of both BMP4 and BMP7. BMP4 alone, and/or silencing GREM1, increased transcriptional activation of peroxisome proliferator-activated receptor γ and promoted the preadipocytes to assume an oxidative beige/brown adipose phenotype including markers of increased mitochondria and PGC1α. Driving white adipose differentiation inhibited the beige/brown markers, suggesting the presence of multipotent adipogenic precursor cells. However, silencing GREM1 and/or adding BMP4 during white adipogenic differentiation reactivated beige/brown markers, suggesting that increased BMP4 preferentially regulates the beige/brown phenotype. Thus, BMP4, secreted by white adipose cells, is an integral feedback regulator of both white and beige adipogenic commitment and differentiation, and resistance to BMP4 by GREM1 characterizes hypertrophic obesity.
authors.affiliation: Lundberg Laboratory for Diabetes Research, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Birgit
authors.initials: B
authors.lastname: Gustafson
authors.affiliation: Lundberg Laboratory for Diabetes Research, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Hammarstedt
authors.affiliation: Lundberg Laboratory for Diabetes Research, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Shahram
authors.initials: S
authors.lastname: Hedjazifar
authors.affiliation: Lundberg Laboratory for Diabetes Research, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Hoffmann
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Per-Arne
authors.initials: PA
authors.lastname: Svensson
authors.affiliation: MedImmune, LLC, Gaithersburg, MD.
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
authors.affiliation: MedImmune, LLC, Gaithersburg, MD.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rondinone
authors.affiliation: Lundberg Laboratory for Diabetes Research, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden ulf.smith@medic.gu.se.
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
mesh_terms: D050156:Adipogenesis / Q000235:genetics / Q000502:physiology*; D000273:Adipose Tissue / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000328:Adult; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C486602:CHRDL1 protein, human; D005136:Eye Proteins; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering