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

Schulz TJ, Graja A, Huang TL, Xue R, An D, Poehle-Kronawitter S, Lynes MD, Tolkachov A, O'Sullivan LE, Hirshman MF, Schupp M, Goodyear LJ, Mishina Y, Tseng YH - Diabetologia (2016)

Bottom Line: Conditional deletion of Bmpr1a using the aP2 (also known as Fabp4)-Cre strain resulted in a complex phenotype.Moreover, knockouts displayed significant reduction of variables of adipose tissue inflammation.Co-cultivation of macrophages with pre-adipocytes lacking Bmpr1a markedly reduced expression of proinflammatory genes.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Loss of Bmpr1a in adipose tissue improves insulin sensitivity. (a, b) ITT in 38-week-old mice maintained on a normal chow diet (a) (AUC: p = 0.0286) or in 40-week-old mice maintained on 45%HFD from 4–5 weeks of age (b) (AUC: p = 0.0043). Diamonds, control mice; squares, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 4 for both groups in a; n = 5 for control and n = 6 for knockout in b). *p < 0.05 and **p < 0.01 compared with control mice (c, d) GTT in 50-week-old mice fed either a normal chow diet (c) (AUC: p = 0.3429) or 45%HFD (d) (AUC: p = 0.6095). Diamonds, control mice; squares, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 4 for both groups in c; n = 5 for control and n = 6 for knockout in d). (e, f) Western blot analysis of insulin-stimulated activation of the insulin signalling pathway in iWAT (e) and eWAT (f). Levels of the phosphorylated forms of insulin receptor-β (p-InsRβ), insulin receptor substrate (p-IRS)1, protein kinase B (p-Akt) and extracellular-signal regulated kinase (p-ERK) were detected and normalised to basal expression of β-tubulin (β-Tub). Quantification is shown in ESM Fig. 7. (g, h) Unstimulated (Basal) and insulin-stimulated glucose uptake (Insulin) in BAT (g) and tibialis anterior skeletal muscle (h). White bars, control mice; grey bars, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 7 for basal control; n = 6 for basal knockout; n = 8 for insulin control; n = 6 for insulin knockout). **p < 0.01 compared with control mice
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Fig1: Loss of Bmpr1a in adipose tissue improves insulin sensitivity. (a, b) ITT in 38-week-old mice maintained on a normal chow diet (a) (AUC: p = 0.0286) or in 40-week-old mice maintained on 45%HFD from 4–5 weeks of age (b) (AUC: p = 0.0043). Diamonds, control mice; squares, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 4 for both groups in a; n = 5 for control and n = 6 for knockout in b). *p < 0.05 and **p < 0.01 compared with control mice (c, d) GTT in 50-week-old mice fed either a normal chow diet (c) (AUC: p = 0.3429) or 45%HFD (d) (AUC: p = 0.6095). Diamonds, control mice; squares, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 4 for both groups in c; n = 5 for control and n = 6 for knockout in d). (e, f) Western blot analysis of insulin-stimulated activation of the insulin signalling pathway in iWAT (e) and eWAT (f). Levels of the phosphorylated forms of insulin receptor-β (p-InsRβ), insulin receptor substrate (p-IRS)1, protein kinase B (p-Akt) and extracellular-signal regulated kinase (p-ERK) were detected and normalised to basal expression of β-tubulin (β-Tub). Quantification is shown in ESM Fig. 7. (g, h) Unstimulated (Basal) and insulin-stimulated glucose uptake (Insulin) in BAT (g) and tibialis anterior skeletal muscle (h). White bars, control mice; grey bars, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 7 for basal control; n = 6 for basal knockout; n = 8 for insulin control; n = 6 for insulin knockout). **p < 0.01 compared with control mice

Mentions: To analyse glucose homeostasis in more detail, we conducted ITTs and GTTs in mice either maintained on a normal diet or on an HFD containing 45% of energy from fat (45%HFD). Interestingly, aP2-Bmpr1a-KO mice on both diets displayed improved insulin sensitivity (Fig. 1a, b) and similar results were obtained for aged, but not young, mice maintained on 60%HFD (ESM Fig. 5). Glucose tolerance, on the other hand, showed a trend towards (but not significant) improvement on either diet when assessed at 52 weeks of age (Fig. 1c, d). Blood glucose, serum insulin and lipid levels remained unchanged at this age, although insulin levels tended to be lower in knockout mice on both diets (ESM Fig. 6).Fig. 1


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

Schulz TJ, Graja A, Huang TL, Xue R, An D, Poehle-Kronawitter S, Lynes MD, Tolkachov A, O'Sullivan LE, Hirshman MF, Schupp M, Goodyear LJ, Mishina Y, Tseng YH - Diabetologia (2016)

Loss of Bmpr1a in adipose tissue improves insulin sensitivity. (a, b) ITT in 38-week-old mice maintained on a normal chow diet (a) (AUC: p = 0.0286) or in 40-week-old mice maintained on 45%HFD from 4–5 weeks of age (b) (AUC: p = 0.0043). Diamonds, control mice; squares, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 4 for both groups in a; n = 5 for control and n = 6 for knockout in b). *p < 0.05 and **p < 0.01 compared with control mice (c, d) GTT in 50-week-old mice fed either a normal chow diet (c) (AUC: p = 0.3429) or 45%HFD (d) (AUC: p = 0.6095). Diamonds, control mice; squares, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 4 for both groups in c; n = 5 for control and n = 6 for knockout in d). (e, f) Western blot analysis of insulin-stimulated activation of the insulin signalling pathway in iWAT (e) and eWAT (f). Levels of the phosphorylated forms of insulin receptor-β (p-InsRβ), insulin receptor substrate (p-IRS)1, protein kinase B (p-Akt) and extracellular-signal regulated kinase (p-ERK) were detected and normalised to basal expression of β-tubulin (β-Tub). Quantification is shown in ESM Fig. 7. (g, h) Unstimulated (Basal) and insulin-stimulated glucose uptake (Insulin) in BAT (g) and tibialis anterior skeletal muscle (h). White bars, control mice; grey bars, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 7 for basal control; n = 6 for basal knockout; n = 8 for insulin control; n = 6 for insulin knockout). **p < 0.01 compared with control mice
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Fig1: Loss of Bmpr1a in adipose tissue improves insulin sensitivity. (a, b) ITT in 38-week-old mice maintained on a normal chow diet (a) (AUC: p = 0.0286) or in 40-week-old mice maintained on 45%HFD from 4–5 weeks of age (b) (AUC: p = 0.0043). Diamonds, control mice; squares, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 4 for both groups in a; n = 5 for control and n = 6 for knockout in b). *p < 0.05 and **p < 0.01 compared with control mice (c, d) GTT in 50-week-old mice fed either a normal chow diet (c) (AUC: p = 0.3429) or 45%HFD (d) (AUC: p = 0.6095). Diamonds, control mice; squares, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 4 for both groups in c; n = 5 for control and n = 6 for knockout in d). (e, f) Western blot analysis of insulin-stimulated activation of the insulin signalling pathway in iWAT (e) and eWAT (f). Levels of the phosphorylated forms of insulin receptor-β (p-InsRβ), insulin receptor substrate (p-IRS)1, protein kinase B (p-Akt) and extracellular-signal regulated kinase (p-ERK) were detected and normalised to basal expression of β-tubulin (β-Tub). Quantification is shown in ESM Fig. 7. (g, h) Unstimulated (Basal) and insulin-stimulated glucose uptake (Insulin) in BAT (g) and tibialis anterior skeletal muscle (h). White bars, control mice; grey bars, aP2-Bmpr1a-KO mice. Data are shown as means ± SEM (n = 7 for basal control; n = 6 for basal knockout; n = 8 for insulin control; n = 6 for insulin knockout). **p < 0.01 compared with control mice
Mentions: To analyse glucose homeostasis in more detail, we conducted ITTs and GTTs in mice either maintained on a normal diet or on an HFD containing 45% of energy from fat (45%HFD). Interestingly, aP2-Bmpr1a-KO mice on both diets displayed improved insulin sensitivity (Fig. 1a, b) and similar results were obtained for aged, but not young, mice maintained on 60%HFD (ESM Fig. 5). Glucose tolerance, on the other hand, showed a trend towards (but not significant) improvement on either diet when assessed at 52 weeks of age (Fig. 1c, d). Blood glucose, serum insulin and lipid levels remained unchanged at this age, although insulin levels tended to be lower in knockout mice on both diets (ESM Fig. 6).Fig. 1

Bottom Line: Conditional deletion of Bmpr1a using the aP2 (also known as Fabp4)-Cre strain resulted in a complex phenotype.Moreover, knockouts displayed significant reduction of variables of adipose tissue inflammation.Co-cultivation of macrophages with pre-adipocytes lacking Bmpr1a markedly reduced expression of proinflammatory genes.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus