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

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 homeost... Full description

Journal Title: Diabetologia 2016-05-21, Vol.59 (8), p.1769-1777
Main Author: Schulz, Tim J
Other Authors: Graja, Antonia , Huang, Tian Lian , Xue, Ruidan , An, Ding , Poehle-Kronawitter, Sophie , Lynes, Matthew D , Tolkachov, Alexander , O’Sullivan, Lindsay E , Hirshman, Michael F , Schupp, Michael , Goodyear, Laurie J , Mishina, Yuji , Tseng, Yu-Hua
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
ID: ISSN: 0012-186X
Link: https://www.ncbi.nlm.nih.gov/pubmed/27209464
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4930470
title: Loss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance
format: Article
creator:
  • Schulz, Tim J
  • Graja, Antonia
  • Huang, Tian Lian
  • Xue, Ruidan
  • An, Ding
  • Poehle-Kronawitter, Sophie
  • Lynes, Matthew D
  • Tolkachov, Alexander
  • O’Sullivan, Lindsay E
  • Hirshman, Michael F
  • Schupp, Michael
  • Goodyear, Laurie J
  • Mishina, Yuji
  • Tseng, Yu-Hua
subjects:
  • Adipocytes - metabolism
  • Adipose tissue
  • Adipose Tissue - metabolism
  • Adipose tissues
  • Ageing
  • Analysis
  • Animals
  • Article
  • Bone Morphogenetic Protein Receptors, Type I - genetics
  • Bone Morphogenetic Protein Receptors, Type I - metabolism
  • Bone morphogenetic proteins
  • Development and progression
  • Dextrose
  • Diabetes
  • Diet, High-Fat - adverse effects
  • Endocrinology
  • Fatty Acids, Nonesterified - blood
  • Gene expression
  • Glucose
  • Glucose - metabolism
  • Human Physiology
  • Insulin - blood
  • Insulin resistance
  • Insulin Resistance - genetics
  • Insulin Resistance - physiology
  • Insulin sensitivity
  • Interleukin-6 - blood
  • Internal Medicine
  • Macrophage infiltration
  • Macrophages
  • Medicine
  • Medicine & Public Health
  • Metabolic Diseases
  • Metabolism
  • Mice
  • Mice, Knockout
  • Physiological aspects
  • Tumor Necrosis Factor-alpha - blood
ispartof: Diabetologia, 2016-05-21, Vol.59 (8), p.1769-1777
description: 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.
language: eng
source:
identifier: ISSN: 0012-186X
fulltext: no_fulltext
issn:
  • 0012-186X
  • 1432-0428
url: Link


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titleLoss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance
creatorSchulz, Tim J ; Graja, Antonia ; Huang, Tian Lian ; Xue, Ruidan ; An, Ding ; Poehle-Kronawitter, Sophie ; Lynes, Matthew D ; Tolkachov, Alexander ; O’Sullivan, Lindsay E ; Hirshman, Michael F ; Schupp, Michael ; Goodyear, Laurie J ; Mishina, Yuji ; Tseng, Yu-Hua
creatorcontribSchulz, Tim J ; Graja, Antonia ; Huang, Tian Lian ; Xue, Ruidan ; An, Ding ; Poehle-Kronawitter, Sophie ; Lynes, Matthew D ; Tolkachov, Alexander ; O’Sullivan, Lindsay E ; Hirshman, Michael F ; Schupp, Michael ; Goodyear, Laurie J ; Mishina, Yuji ; Tseng, Yu-Hua
descriptionAims/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.
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subjectAdipocytes - metabolism ; Adipose tissue ; Adipose Tissue - metabolism ; Adipose tissues ; Ageing ; Analysis ; Animals ; Article ; Bone Morphogenetic Protein Receptors, Type I - genetics ; Bone Morphogenetic Protein Receptors, Type I - metabolism ; Bone morphogenetic proteins ; Development and progression ; Dextrose ; Diabetes ; Diet, High-Fat - adverse effects ; Endocrinology ; Fatty Acids, Nonesterified - blood ; Gene expression ; Glucose ; Glucose - metabolism ; Human Physiology ; Insulin - blood ; Insulin resistance ; Insulin Resistance - genetics ; Insulin Resistance - physiology ; Insulin sensitivity ; Interleukin-6 - blood ; Internal Medicine ; Macrophage infiltration ; Macrophages ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Metabolism ; Mice ; Mice, Knockout ; Physiological aspects ; Tumor Necrosis Factor-alpha - blood
ispartofDiabetologia, 2016-05-21, Vol.59 (8), p.1769-1777
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8O’Sullivan, Lindsay E
9Hirshman, Michael F
10Schupp, Michael
11Goodyear, Laurie J
12Mishina, Yuji
13Tseng, Yu-Hua
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descriptionAims/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.
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14Diet, High-Fat - adverse effects
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20Human Physiology
21Insulin - blood
22Insulin resistance
23Insulin Resistance - genetics
24Insulin Resistance - physiology
25Insulin sensitivity
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titleLoss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance
authorSchulz, Tim J ; Graja, Antonia ; Huang, Tian Lian ; Xue, Ruidan ; An, Ding ; Poehle-Kronawitter, Sophie ; Lynes, Matthew D ; Tolkachov, Alexander ; O’Sullivan, Lindsay E ; Hirshman, Michael F ; Schupp, Michael ; Goodyear, Laurie J ; Mishina, Yuji ; Tseng, Yu-Hua
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1Adipose tissue
2Adipose Tissue - metabolism
3Adipose tissues
4Ageing
5Analysis
6Animals
7Article
8Bone Morphogenetic Protein Receptors, Type I - genetics
9Bone Morphogenetic Protein Receptors, Type I - metabolism
10Bone morphogenetic proteins
11Development and progression
12Dextrose
13Diabetes
14Diet, High-Fat - adverse effects
15Endocrinology
16Fatty Acids, Nonesterified - blood
17Gene expression
18Glucose
19Glucose - metabolism
20Human Physiology
21Insulin - blood
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6Lynes, Matthew D
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8O’Sullivan, Lindsay E
9Hirshman, Michael F
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7Tolkachov, Alexander
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abstractAims/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.
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