Abstract Body: Obesity affects over 40% of U.S. adults and is a major driver of cardiometabolic disease. A defining feature of obesity is excessive extracellular matrix (ECM) accumulation in white adipose tissue (WAT), which leads to fibrosis, restricts adipocyte plasticity, and suppresses the recruitment of thermogenic beige adipocytes. While ECM remodeling is increasingly recognized as a critical regulator of adipose tissue function, the molecular pathways that coordinate collagen maturation and beige adipocyte recruitment remain poorly understood.
Our study focuses on two structurally related ECM-associated proteins, procollagen C-proteinase enhancer 1 (Pcpe1) and Pcpe2, which have recently emerged as potential regulators of adipose tissue remodeling. Pcpe1 is a well-characterized enhancer of BMP1-mediated procollagen cleavage and is elevated in obesity, where it promotes fibrotic responses in multiple tissues. In contrast, Pcpe2 is a less studied glycoprotein that is also upregulated during diet-induced obesity but uniquely inhibits BMP1-dependent procollagen processing. These observations suggest that despite their structural similarity, Pcpe1 and Pcpe2 may exert opposing effects on collagen maturation and adipose tissue remodeling.
To elucidate the specific roles of Pcpe1 and Pcpe2 in WAT remodeling and expansion, we investigated adipose-specific knockout mouse models, Adipo+ Pcpe1^KO and Adipo+ Pcpe2^KO. Preliminary data demonstrate that Pcpe1 and Pcpe2 produces strikingly different effects on ECM composition and beiging. Pcpe1 deletion decreased collagen 1 and 3 mRNA by 52% and by 67%, and reduced beige adipocyte marker (Ucp1) mRNA by 95%. In contrast, Pcpe2 deletion markedly increased collagen (Col1 and Col3) mRNA expression by 2.52 and 15.2-fold. Likewise, Pcpe2 deletion also significantly enhanced beige adipocyte marker (Ucp1) mRNA by 4.4 fold, which was also further validated through histological analyses of Ucp1 in WAT. Importantly, Pcpe2 deletion also protected mice from diet-induced obesity by reducing adiposity, improving glucose tolerance and insulin sensitivity, and increasing whole-body energy expenditure. Intrestingly, deletion of either Pcpe1 or Pcpe2 had same effect on lipogenic genes expression such as Fasn, Srebp1c expression.
Collectively, our findings indicate that Pcpe1 and Pcpe2 have specific functional overlap but largely play distinct opposing roles in regulating WAT ECM remodeling and enhancement of WAT beiging during obesity.