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LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion.

Loh NY, Neville MJ, Marinou K, Hardcastle SA, Fielding BA, Duncan EL, McCarthy MI, Tobias JH, Gregson CL, Karpe F, Christodoulides C - Cell Metab. (2015)

Bottom Line: Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis.These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology.They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.

View Article: PubMed Central - PubMed

Affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK.

No MeSH data available.


Related in: MedlinePlus

LRP5-KD in Abdominal and Gluteal SVCs Dose-Dependently Modulates β-Catenin Signaling(A) Protein densitometry of LRP5, pLRP5/6-S1490, and active β-catenin in Abdo-sh401, Abdo-sh400, Glut-sh401, and Glut-sh400 SVCs. Densitometry data were normalized to α-tubulin and are shown relative to their respective shCON levels. n = 3–4 independent experiments.(B) Gene expression profiling of β-catenin target genes in Abdo-sh401, Abdo-sh400, Glut-sh401, and Glut-sh400 SVCs. mRNA data were normalized to 18S and are shown relative to their respective shCON levels. n = 4–7 independent experiments.(C) Treatment with the β-catenin small-molecule inhibitor iCRT14 dose-dependently modulates TOPflash promoter activity, adipogenesis, and proliferation in immortalized abdominal and gluteal SVCs (n = 6–7 replicates). Histogram data are means ± SEM. ∗,#p < 0.05, ∗∗,##p < 0.01, ∗∗∗p < 0.001. ∗,∗∗,∗∗∗ within group comparisons; #,## between group comparisons.
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fig4: LRP5-KD in Abdominal and Gluteal SVCs Dose-Dependently Modulates β-Catenin Signaling(A) Protein densitometry of LRP5, pLRP5/6-S1490, and active β-catenin in Abdo-sh401, Abdo-sh400, Glut-sh401, and Glut-sh400 SVCs. Densitometry data were normalized to α-tubulin and are shown relative to their respective shCON levels. n = 3–4 independent experiments.(B) Gene expression profiling of β-catenin target genes in Abdo-sh401, Abdo-sh400, Glut-sh401, and Glut-sh400 SVCs. mRNA data were normalized to 18S and are shown relative to their respective shCON levels. n = 4–7 independent experiments.(C) Treatment with the β-catenin small-molecule inhibitor iCRT14 dose-dependently modulates TOPflash promoter activity, adipogenesis, and proliferation in immortalized abdominal and gluteal SVCs (n = 6–7 replicates). Histogram data are means ± SEM. ∗,#p < 0.05, ∗∗,##p < 0.01, ∗∗∗p < 0.001. ∗,∗∗,∗∗∗ within group comparisons; #,## between group comparisons.

Mentions: β-catenin has been shown to dose-dependently modulate target gene expression and stem/progenitor cell cycling and fate-determination (Hirata et al., 2013; Kielman et al., 2002; Luis et al., 2011). Given the graded effects of LRP5 KD on abdominal and gluteal SVC proliferation and differentiation, we examined whether active β-catenin levels and β-catenin target genes were regulated in a dose-like fashion. This was indeed the case (Figures 4A and 4B). Mirroring these findings, selectively attenuating β-catenin transcriptional activity with use of the small-molecule inhibitor iCRT14 (Gonsalves et al., 2011) dose-dependently impaired adipogenesis in immortalized gluteal SVCs (Figure 4C). In contrast, low-dose iCTR14 (1 μM) enhanced adipogenesis in abdominal progenitors while higher dose (10 μM) impaired differentiation, albeit to a lesser extent than the equivalent dose in gluteal cells. Accordingly, iCTR14-induced inhibition of β-catenin-dependent promoter activity was more pronounced in gluteal than abdominal SVCs. iCRT14 also dose-dependently impaired adipose progenitor proliferation. As expected, this effect was more marked in gluteal versus abdominal cells (Figure 4C). We conclude that the biological effects of LRP5 KD in adipose progenitors are driven by dose-dependent reductions in β-catenin transcriptional activity, which, for an equivalent decrease in LRP5 gene dosage, is more potently blocked in gluteal than abdominal SVCs.


LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion.

Loh NY, Neville MJ, Marinou K, Hardcastle SA, Fielding BA, Duncan EL, McCarthy MI, Tobias JH, Gregson CL, Karpe F, Christodoulides C - Cell Metab. (2015)

LRP5-KD in Abdominal and Gluteal SVCs Dose-Dependently Modulates β-Catenin Signaling(A) Protein densitometry of LRP5, pLRP5/6-S1490, and active β-catenin in Abdo-sh401, Abdo-sh400, Glut-sh401, and Glut-sh400 SVCs. Densitometry data were normalized to α-tubulin and are shown relative to their respective shCON levels. n = 3–4 independent experiments.(B) Gene expression profiling of β-catenin target genes in Abdo-sh401, Abdo-sh400, Glut-sh401, and Glut-sh400 SVCs. mRNA data were normalized to 18S and are shown relative to their respective shCON levels. n = 4–7 independent experiments.(C) Treatment with the β-catenin small-molecule inhibitor iCRT14 dose-dependently modulates TOPflash promoter activity, adipogenesis, and proliferation in immortalized abdominal and gluteal SVCs (n = 6–7 replicates). Histogram data are means ± SEM. ∗,#p < 0.05, ∗∗,##p < 0.01, ∗∗∗p < 0.001. ∗,∗∗,∗∗∗ within group comparisons; #,## between group comparisons.
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fig4: LRP5-KD in Abdominal and Gluteal SVCs Dose-Dependently Modulates β-Catenin Signaling(A) Protein densitometry of LRP5, pLRP5/6-S1490, and active β-catenin in Abdo-sh401, Abdo-sh400, Glut-sh401, and Glut-sh400 SVCs. Densitometry data were normalized to α-tubulin and are shown relative to their respective shCON levels. n = 3–4 independent experiments.(B) Gene expression profiling of β-catenin target genes in Abdo-sh401, Abdo-sh400, Glut-sh401, and Glut-sh400 SVCs. mRNA data were normalized to 18S and are shown relative to their respective shCON levels. n = 4–7 independent experiments.(C) Treatment with the β-catenin small-molecule inhibitor iCRT14 dose-dependently modulates TOPflash promoter activity, adipogenesis, and proliferation in immortalized abdominal and gluteal SVCs (n = 6–7 replicates). Histogram data are means ± SEM. ∗,#p < 0.05, ∗∗,##p < 0.01, ∗∗∗p < 0.001. ∗,∗∗,∗∗∗ within group comparisons; #,## between group comparisons.
Mentions: β-catenin has been shown to dose-dependently modulate target gene expression and stem/progenitor cell cycling and fate-determination (Hirata et al., 2013; Kielman et al., 2002; Luis et al., 2011). Given the graded effects of LRP5 KD on abdominal and gluteal SVC proliferation and differentiation, we examined whether active β-catenin levels and β-catenin target genes were regulated in a dose-like fashion. This was indeed the case (Figures 4A and 4B). Mirroring these findings, selectively attenuating β-catenin transcriptional activity with use of the small-molecule inhibitor iCRT14 (Gonsalves et al., 2011) dose-dependently impaired adipogenesis in immortalized gluteal SVCs (Figure 4C). In contrast, low-dose iCTR14 (1 μM) enhanced adipogenesis in abdominal progenitors while higher dose (10 μM) impaired differentiation, albeit to a lesser extent than the equivalent dose in gluteal cells. Accordingly, iCTR14-induced inhibition of β-catenin-dependent promoter activity was more pronounced in gluteal than abdominal SVCs. iCRT14 also dose-dependently impaired adipose progenitor proliferation. As expected, this effect was more marked in gluteal versus abdominal cells (Figure 4C). We conclude that the biological effects of LRP5 KD in adipose progenitors are driven by dose-dependent reductions in β-catenin transcriptional activity, which, for an equivalent decrease in LRP5 gene dosage, is more potently blocked in gluteal than abdominal SVCs.

Bottom Line: Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis.These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology.They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.

View Article: PubMed Central - PubMed

Affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK.

No MeSH data available.


Related in: MedlinePlus