title: Loss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance.
abstract: Adipose tissue dysfunction is a prime risk factor for the development of metabolic disease. Bone morphogenetic proteins (BMPs) have previously been implicated in adipocyte formation. Here, we investigate the role of BMP signalling in adipose tissue health and systemic glucose homeostasis.
  
  
  
  We employed the Cre/loxP system to generate mouse models with conditional ablation of BMP receptor 1A in differentiating and mature adipocytes, as well as tissue-resident myeloid cells. Metabolic variables were assessed by glucose and insulin tolerance testing, insulin-stimulated glucose uptake and gene expression analysis.
  
  
  
  Conditional deletion of Bmpr1a using the aP2 (also known as Fabp4)-Cre strain resulted in a complex phenotype. Knockout mice were clearly resistant to age-related impairment of insulin sensitivity during normal and high-fat-diet feeding and showed significantly improved insulin-stimulated glucose uptake in brown adipose tissue and skeletal muscle. Moreover, knockouts displayed significant reduction of variables of adipose tissue inflammation. Deletion of Bmpr1a in myeloid cells had no impact on insulin sensitivity, while ablation of Bmpr1a in mature adipocytes partially recapitulated the initial phenotype from aP2-Cre driven deletion. Co-cultivation of macrophages with pre-adipocytes lacking Bmpr1a markedly reduced expression of proinflammatory genes.
  
  
  
  Our findings show that altered BMP signalling in adipose tissue affects the tissue's metabolic properties and systemic insulin resistance by altering the pattern of immune cell infiltration. The phenotype is due to ablation of Bmpr1a specifically in pre-adipocytes and maturing adipocytes rather than an immune cell-autonomous effect. Mechanistically, we provide evidence for a BMP-mediated direct crosstalk between pre-adipocytes and macrophages.
authors.affiliation: German Institute of Human Nutrition (DIfE), Department of Adipocyte Development and Nutrition, 114-116, Arthur-Scheunert Allee, 14558, Potsdam-Nuthetal, Germany. Tim.Schulz@dife.de.|Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA. Tim.Schulz@dife.de.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany. Tim.Schulz@dife.de.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Schulz
authors.affiliation: German Institute of Human Nutrition (DIfE), Department of Adipocyte Development and Nutrition, 114-116, Arthur-Scheunert Allee, 14558, Potsdam-Nuthetal, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Graja
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Tian Lian
authors.initials: TL
authors.lastname: Huang
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Ruidan
authors.initials: R
authors.lastname: Xue
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: An
authors.affiliation: German Institute of Human Nutrition (DIfE), Department of Adipocyte Development and Nutrition, 114-116, Arthur-Scheunert Allee, 14558, Potsdam-Nuthetal, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Poehle-Kronawitter
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lynes
authors.affiliation: Charité University School of Medicine, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tolkachov
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: O'Sullivan
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Hirshman
authors.affiliation: Charité University School of Medicine, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schupp
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Goodyear
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA. Yu-Hua.Tseng@joslin.harvard.edu.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Yu-Hua.Tseng@joslin.harvard.edu.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Tseng
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D052005:Bone Morphogenetic Protein Receptors, Type I; D005947:Glucose
keywords: Adipose tissue; Ageing; Bone morphogenetic proteins; Insulin sensitivity; Macrophage infiltration