Abstract
The visceral (VIS) and subcutaneous (SQ) fat pads are developmentally distinct white adipose tissue depots and contribute differently to inflammation and insulin resistance associated with obesity. The basic helix-loop-helix transcriptional regulator, transcription factor 21 (TCF21), is a marker gene for white adipose tissues and is abundantly expressed in VIS-derived adipose stem cells (ASCs), but not in SQ-derived ASCs. However, TCF21's role in regulating fat depot-specific gene expression and function is incompletely understood. Here, using siRNA-mediated Tcf21 knockdowns and lentiviral gene transfer of TCF21 in mouse ASCs, we demonstrate that TCF21 is required for the VIS ASC-specific expression of interleukin 6 (IL6), a key cytokine that contributes to the proinflammatory nature of VIS depots. Concurrently, TCF21 promotes MMP-dependent collagen degradation and type IV collagen deposition through the regulation of the extracellular matrix (ECM) modifiers, matrix metalloproteinase (MMP) 2, MMP13, and tissue inhibitor of MMP1 (TIMP1), as well as collagen type IV α1 chain (COL4A1) in VIS ASCs. We also found that although IL6 mediates the expression of Mmp13 and Timp1 in VIS ASCs, the TCF21-dependent expression of Mmp2 and Col4a1 is IL6-independent. These results suggest that TCF21 contributes to the proinflammatory environment in VIS fat depots and to active ECM remodeling of these depots by regulating IL6 expression and MMP-dependent ECM remodeling in a spatiotemporally coordinated manner.
Highlights
The visceral (VIS) and subcutaneous (SQ) fat pads are developmentally distinct white adipose tissue depots and contribute differently to inflammation and insulin resistance associated with obesity
To define the transcriptional network of VIS adipose stem cells (ASCs) responsible for the co-expression of interleukin 6 (IL6) and a subset of matrix metalloproteinase (MMP) and tissue inhibitors of MMPs (TIMPs), we focused on transcription factor 21 (TCF21), a basic helix–loop– helix transcription factor abundantly expressed in VIS ASCs but barely in SQ ASCs
The mRNA levels of Il6 and tissue inhibitor of matrix metalloproteinase-1 (Timp1) were preferentially expressed in VIS ASCs, whereas those of Mmp2 and Mmp14 were similar between ASCs of both depots (Fig. 1A)
Summary
Our previous work showed the depot-specific transcriptomes of mouse WAT Sca1high ASCs using whole-genome RNA-seq [9]. Examined the effect of siRNA-mediated TCF21 knockdown on IL6 transcription and protein expression in isolated mouse VIS ASCs. Two independent siRNA oligonucleotides (designed within Tcf coding regions) suppressed mRNA levels by 40 and 75%, respectively (Fig. 2A). In cultured VIS ASCs, Tcf knockdown reduced the expression of Col4a1 but had no impact on Col1a1 or Col3a1 (Fig. 4A) Despite the inhibitory effects on the expression of MMP13 and TIMP1, the presence of IL6-neutralizing antibody did not change either type IV collagen deposition or type I collagen degradation (Fig. 5B), suggesting that TCF21 promotes collagenolytic ECM remodeling in a IL6-independent manner
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