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Diabetologia. 2016 Aug;59(8):1769-77. doi: 10.1007/s00125-016-3990-8. Epub 2016 May 21.

Loss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance.

Author information

1
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.
2
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA. Tim.Schulz@dife.de.
3
German Center for Diabetes Research (DZD), München-Neuherberg, Germany. Tim.Schulz@dife.de.
4
German Institute of Human Nutrition (DIfE), Department of Adipocyte Development and Nutrition, 114-116, Arthur-Scheunert Allee, 14558, Potsdam-Nuthetal, Germany.
5
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA.
6
Charité University School of Medicine, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, Germany.
7
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
8
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.
9
Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Yu-Hua.Tseng@joslin.harvard.edu.

Abstract

AIMS/HYPOTHESIS:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS/INTERPRETATION:

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.

KEYWORDS:

Adipose tissue; Ageing; Bone morphogenetic proteins; Insulin sensitivity; Macrophage infiltration

PMID:
27209464
PMCID:
PMC4930470
DOI:
10.1007/s00125-016-3990-8
[Indexed for MEDLINE]
Free PMC Article

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