Laboratory of Nutrigenomics and Growth Biology, Department of Animal Sciences, Washington State University, Pullman, USA.
School of Food Science, Washington State University, Pullman, USA.
Biochim Biophys Acta Mol Basis Dis. 2022 Sep 1;1868(9):166454. doi: 10.1016/j.bbadis.2022.166454. Epub 2022 May 26.
Collagen is the main component of connective tissue surrounding adipocytes. Collagen cross-linking affects adipose remodeling, which is crucial for maintaining function and metabolic homeostasis of adipose tissue. However, the effects of obesity on collagen cross-linking and adipose fibrosis remain to be examined. Therefore, the objective of this study was to investigate obesity-induced collagen cross-linking in adipose tissue and explore the underlying mechanisms. We found that obesity increased mature nonreducible collagen cross-linking in white adipose tissue (WAT) of mice, which was associated with inhibition of AMPK, up-regulation of transforming growth factor-β (TGF-β) signaling and the expression of lysyl oxidase (LOX), a key enzyme catalyzing the synthesis of mature cross-linking products. In SVCs and 3T3-L1 adipocytes, AMPK activation by metformin or AICAR inhibited TGF-β1-induced fibrogenesis and expression of LOX, which was further confirmed by ectopic expression of AMPK WT and K45R mutant. Consistently, in vivo, knocking out AMPK increased fibrosis and collagen cross-linking. Our study showed that AMPK downregulation due to obesity increases TGF-β signaling and LOX expression, which enhances adipose fibrosis and collagen cross-linking. Thus, AMPK is a therapeutic target for ameliorating the obesity-induced fibrosis, improving metabolic health of adipose tissue.
胶原蛋白是围绕脂肪细胞的结缔组织的主要成分。胶原蛋白交联会影响脂肪重塑，这对于维持脂肪组织的功能和代谢稳态至关重要。然而，肥胖对胶原蛋白交联和脂肪纤维化的影响仍需研究。因此，本研究旨在探讨肥胖诱导的脂肪组织胶原蛋白交联，并探索其潜在机制。我们发现肥胖增加了小鼠白色脂肪组织（WAT）中成熟的不可还原型胶原蛋白交联，这与 AMPK 的抑制、转化生长因子-β（TGF-β）信号的上调以及赖氨酰氧化酶（LOX）的表达有关，LOX 是催化成熟交联产物合成的关键酶。在 SVCs 和 3T3-L1 脂肪细胞中，二甲双胍或 AICAR 通过激活 AMPK 抑制 TGF-β1 诱导的纤维化和 LOX 的表达，这一结论通过 AMPK WT 和 K45R 突变体的异位表达进一步得到证实。同样，在体内，敲除 AMPK 会增加纤维化和胶原蛋白交联。我们的研究表明，肥胖导致的 AMPK 下调会增加 TGF-β 信号和 LOX 的表达，从而增强脂肪纤维化和胶原蛋白交联。因此，AMPK 是改善肥胖诱导的纤维化、改善脂肪组织代谢健康的治疗靶点。
