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Wnt antagonist secreted frizzled-related protein 4 upregulates adipogenic differentiation in human adipose tissue-derived mesenchymal stem cells.

Visweswaran M, Schiefer L, Arfuso F, Dilley RJ, Newsholme P, Dharmarajan A - PLoS ONE (2015)

Bottom Line: We also examined the effect of Wnt inhibition using secreted frizzled-related protein 4 (sFRP4), which we have previously shown to be pro-apoptotic, anti-angiogenic, and anti-tumorigenic.Wnt stimulation in LiCl and BIO-treated ADSCs resulted in a significant reduction (2.7-fold and 12-fold respectively) in lipid accumulation as measured by Oil red O staining while Wnt inhibition with sFRP4 induced a 1.5-fold increase in lipid accumulation.In contrast, the expression of adipogenic proteins (PPARγ, C/EBPα, and acetyl CoA carboxylase) were decreased significantly with LiCl (by 1.6, 2.6, and 1.9-fold respectively) and BIO (by 7, 17, and 5.6-fold respectively) treatments.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.

ABSTRACT
With more than 1.4 billion overweight or obese adults worldwide, obesity and progression of the metabolic syndrome are major health and economic challenges. To address mechanisms of obesity, adipose tissue-derived mesenchymal stem cells (ADSCs) are being studied to detail the molecular mechanisms involved in adipogenic differentiation. Activation of the Wnt signalling pathway has inhibited adipogenesis from precursor cells. In our study, we examined this anti-adipogenic effect in further detail stimulating Wnt with lithium chloride (LiCl) and 6-bromo indirubin 3'oxime (BIO). We also examined the effect of Wnt inhibition using secreted frizzled-related protein 4 (sFRP4), which we have previously shown to be pro-apoptotic, anti-angiogenic, and anti-tumorigenic. Wnt stimulation in LiCl and BIO-treated ADSCs resulted in a significant reduction (2.7-fold and 12-fold respectively) in lipid accumulation as measured by Oil red O staining while Wnt inhibition with sFRP4 induced a 1.5-fold increase in lipid accumulation. Furthermore, there was significant 1.2-fold increase in peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha (C/EBPα), and 1.3-fold increase in acetyl CoA carboxylase protein levels. In contrast, the expression of adipogenic proteins (PPARγ, C/EBPα, and acetyl CoA carboxylase) were decreased significantly with LiCl (by 1.6, 2.6, and 1.9-fold respectively) and BIO (by 7, 17, and 5.6-fold respectively) treatments. These investigations demonstrate interplay between Wnt antagonism and Wnt activation during adipogenesis and indicate pathways for therapeutic intervention to control this process.

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Morphology of ADSCs during adipogenic differentiation.At (A) Day 1 and (B) Day 7. Treatment conditions were (i) non-induced control media, (ii) adipogenic control, (iii) 10mM LiCl, (iv) 0.5μM BIO, (v) 100pg/mL sFRP4, and (vi) 1ng/mL sFRP4 in both (A) and (B). Scale bar = 10μM.
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pone.0118005.g003: Morphology of ADSCs during adipogenic differentiation.At (A) Day 1 and (B) Day 7. Treatment conditions were (i) non-induced control media, (ii) adipogenic control, (iii) 10mM LiCl, (iv) 0.5μM BIO, (v) 100pg/mL sFRP4, and (vi) 1ng/mL sFRP4 in both (A) and (B). Scale bar = 10μM.

Mentions: Irrespective of the treatment conditions, the transformation of morphology from a spindle-like shape into a rounded shape was initiated by Day 1 (Fig. 3A). In all the treatment conditions, the lipid droplets started appearing at Day 4, but by Day 7 there was a further increase seen in lipid droplet content of the sFRP4(1ng/mL)-treated compared to the adipogenic control groups (Fig. 3B). In the treatment groups containing the LiCl and BIO, adipogenesis remained low with lesser lipid droplet content (Fig. 3B). Non-induced ADSCs retained their fibroblastic morphology with no lipid accumulation.


Wnt antagonist secreted frizzled-related protein 4 upregulates adipogenic differentiation in human adipose tissue-derived mesenchymal stem cells.

Visweswaran M, Schiefer L, Arfuso F, Dilley RJ, Newsholme P, Dharmarajan A - PLoS ONE (2015)

Morphology of ADSCs during adipogenic differentiation.At (A) Day 1 and (B) Day 7. Treatment conditions were (i) non-induced control media, (ii) adipogenic control, (iii) 10mM LiCl, (iv) 0.5μM BIO, (v) 100pg/mL sFRP4, and (vi) 1ng/mL sFRP4 in both (A) and (B). Scale bar = 10μM.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4340908&req=5

pone.0118005.g003: Morphology of ADSCs during adipogenic differentiation.At (A) Day 1 and (B) Day 7. Treatment conditions were (i) non-induced control media, (ii) adipogenic control, (iii) 10mM LiCl, (iv) 0.5μM BIO, (v) 100pg/mL sFRP4, and (vi) 1ng/mL sFRP4 in both (A) and (B). Scale bar = 10μM.
Mentions: Irrespective of the treatment conditions, the transformation of morphology from a spindle-like shape into a rounded shape was initiated by Day 1 (Fig. 3A). In all the treatment conditions, the lipid droplets started appearing at Day 4, but by Day 7 there was a further increase seen in lipid droplet content of the sFRP4(1ng/mL)-treated compared to the adipogenic control groups (Fig. 3B). In the treatment groups containing the LiCl and BIO, adipogenesis remained low with lesser lipid droplet content (Fig. 3B). Non-induced ADSCs retained their fibroblastic morphology with no lipid accumulation.

Bottom Line: We also examined the effect of Wnt inhibition using secreted frizzled-related protein 4 (sFRP4), which we have previously shown to be pro-apoptotic, anti-angiogenic, and anti-tumorigenic.Wnt stimulation in LiCl and BIO-treated ADSCs resulted in a significant reduction (2.7-fold and 12-fold respectively) in lipid accumulation as measured by Oil red O staining while Wnt inhibition with sFRP4 induced a 1.5-fold increase in lipid accumulation.In contrast, the expression of adipogenic proteins (PPARγ, C/EBPα, and acetyl CoA carboxylase) were decreased significantly with LiCl (by 1.6, 2.6, and 1.9-fold respectively) and BIO (by 7, 17, and 5.6-fold respectively) treatments.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.

ABSTRACT
With more than 1.4 billion overweight or obese adults worldwide, obesity and progression of the metabolic syndrome are major health and economic challenges. To address mechanisms of obesity, adipose tissue-derived mesenchymal stem cells (ADSCs) are being studied to detail the molecular mechanisms involved in adipogenic differentiation. Activation of the Wnt signalling pathway has inhibited adipogenesis from precursor cells. In our study, we examined this anti-adipogenic effect in further detail stimulating Wnt with lithium chloride (LiCl) and 6-bromo indirubin 3'oxime (BIO). We also examined the effect of Wnt inhibition using secreted frizzled-related protein 4 (sFRP4), which we have previously shown to be pro-apoptotic, anti-angiogenic, and anti-tumorigenic. Wnt stimulation in LiCl and BIO-treated ADSCs resulted in a significant reduction (2.7-fold and 12-fold respectively) in lipid accumulation as measured by Oil red O staining while Wnt inhibition with sFRP4 induced a 1.5-fold increase in lipid accumulation. Furthermore, there was significant 1.2-fold increase in peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha (C/EBPα), and 1.3-fold increase in acetyl CoA carboxylase protein levels. In contrast, the expression of adipogenic proteins (PPARγ, C/EBPα, and acetyl CoA carboxylase) were decreased significantly with LiCl (by 1.6, 2.6, and 1.9-fold respectively) and BIO (by 7, 17, and 5.6-fold respectively) treatments. These investigations demonstrate interplay between Wnt antagonism and Wnt activation during adipogenesis and indicate pathways for therapeutic intervention to control this process.

Show MeSH
Related in: MedlinePlus