COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1

Simon N Dankel,Matthias Blüher,Gunnar Mellgren,Jørn V Sagen,Arne Dietrich,Jan-Inge Bjune,Hans Jørgen Nielsen,Elise Grytten

doi:10.1038/s41598-020-77406-2

Simon N Dankel, Matthias Blüher + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-77406-2

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Abstract

Fibrillar collagen COL6α3 in adipose tissue has been associated with obesity, inflammation, insulin resistance and cancer. We here aimed to identify novel transcriptional regulators of COL6A3 expression. Based on a transcriptome dataset of adipose tissue, we identified strong correlations for 56 genes with COL6A3 mRNA, including targets of TGF-β/SMAD signaling. Among the identified candidates, the homeobox transcription factor PRRX1 showed a particularly striking co-expression with COL6A3, validated across several different cohorts, including patients with extreme obesity, insulin sensitive and resistant obesity (subcutaneous and omental), after profound fat loss (subcutaneous), and lean controls (subcutaneous). In human and mouse adipose cells, PRRX1 knockdown reduced COL6A3 mRNA and PRRX1 overexpression transactivated a reporter construct with the endogenous human COL6A3 promoter. Stable PRRX1 overexpression in 3T3-L1 cells induced Col6a3 mRNA threefold specifically after adipogenic induction, whereas TGF-β1 treatment upregulated Col6a3 mRNA also in the preadipocyte state. Interestingly, pro-inflammatory stimulus (i.e., TNF-α treatment) decreased PRRX1-mediated Col6a3 transactivation and mRNA expression, supporting a role for this mechanism in the regulation of adipose tissue inflammation. In conclusion, we identified the homeobox factor PRRX1 as a novel transcriptional regulator associated with COL6A3 expression, providing new insight into the regulatory mechanisms of altered adipose tissue function in obesity and insulin resistance.

Highlights

Fibrillar collagen COL6α3 in adipose tissue has been associated with obesity, inflammation, insulin resistance and cancer
SMAD transcription factor (TF) mediate signaling by the transforming growth factor β (TGF-β) superfamily of ligands, including bone morphogenic proteins (BMPs), growth and differentiation factors (GDFs) and TGF-βs, which play a critical role in development and homeostasis from embryogenesis through adulthood[20]
The strong positive correlation for paired related homeobox 1 (PRRX1) and COL6A3 was evident within each subgroup (Figure S1A), and for the change in PRRX1 mRNA in relation to the change in COL6A3 mRNA after profound fat loss (Fig. 1B)

Summary

Introduction

Fibrillar collagen COL6α3 in adipose tissue has been associated with obesity, inflammation, insulin resistance and cancer. We identified the homeobox factor PRRX1 as a novel transcriptional regulator associated with COL6A3 expression, providing new insight into the regulatory mechanisms of altered adipose tissue function in obesity and insulin resistance. Pro-inflammatory macrophages can impair preadipocyte differentiation into mature adipocytes and promote a pro-fibrotic preadipocyte phenotype, in part involving transforming growth factor β (TGF-β) and tumor necrosis factor α (TNF-α) s ignaling[2,3]. Both impaired adipogenesis and increased collagen deposition may disrupt the normal lipid storage capacity of adipose tissue during energy surplus, and lead to glucotoxicity and lipotoxicity[4,5]. Others found that knockdown of COL6A3 in primary human adipocytes suppressed macrophage chemoattractant protein MCP1, supporting pro-inflammatory effects of COL6α316

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