Department of Bioengineering, Temple University, 1947 N. 12th St, Philadelphia, PA, 19122, USA.
Sci Rep. 2021 Nov 2;11(1):21473. doi: 10.1038/s41598-021-00335-1.
In obese adipose tissue (AT), hypertrophic expansion of adipocytes is not matched by new vessel formation, leading to AT hypoxia. As a result, hypoxia inducible factor-1⍺ (HIF-1⍺) accumulates in adipocytes inducing a transcriptional program that upregulates profibrotic genes and biosynthetic enzymes such as lysyl oxidase (LOX) synthesis. This excess synthesis and crosslinking of extracellular matrix (ECM) components cause AT fibrosis. Although fibrosis is a hallmark of obese AT, the role of fibroblasts, cells known to regulate fibrosis in other fibrosis-prone tissues, is not well studied. Here we have developed an in vitro model of AT to study adipocyte-fibroblast crosstalk in a hypoxic environment. Further, this in vitro model was used to investigate the effect of hypoxia on adipocyte mechanical properties via ras homolog gene family member A (RhoA)/Rho-associated coiled-coil kinases (ROCK) signaling pathways. We confirmed that hypoxia creates a diseased phenotype by inhibiting adipocyte maturation and inducing actin stress fiber formation facilitated by myocardin-related transcription factor A (MRTF-A/MKL1) nuclear translocation. This work presents new potential therapeutic targets for obesity by improving adipocyte maturation and limiting mechanical stress in obese AT.
在肥胖的脂肪组织（AT）中，脂肪细胞的肥大扩张与新血管形成不匹配，导致 AT 缺氧。因此，缺氧诱导因子-1α（HIF-1α）在脂肪细胞中积累，诱导一个上调致纤维化基因和生物合成酶的转录程序，如赖氨酰氧化酶（LOX）的合成。细胞外基质（ECM）成分的这种过度合成和交联导致 AT 纤维化。尽管纤维化是肥胖 AT 的一个标志，但已知在其他易纤维化组织中调节纤维化的成纤维细胞的作用尚未得到很好的研究。在这里，我们开发了一种 AT 的体外模型，以研究缺氧环境下脂肪细胞和成纤维细胞之间的串扰。此外，该体外模型还用于研究缺氧对脂肪细胞机械性能的影响，途径是通过 Ras 同源基因家族成员 A（RhoA）/Rho 相关卷曲螺旋激酶（ROCK）信号通路。我们证实，缺氧通过抑制脂肪细胞成熟和诱导肌球蛋白相关转录因子 A（MRTF-A/MKL1）核易位来促进肌动蛋白应激纤维形成，从而产生疾病表型。这项工作通过改善肥胖 AT 中的脂肪细胞成熟和限制机械应激，为肥胖症提供了新的潜在治疗靶点。
