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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.

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