Obesity is a risk factor for multiple diseases, including diabetes, cardiovascular disease, and cancer. Within obese adipose tissue, multiple factors contribute to creating a disease-promoting environment, including metabolic dysfunction, inflammation, and fibrosis. Recent evidence points to fibrotic responses, particularly extracellular matrix remodeling, in playing a highly functional role in the pathogenesis of obesity. Fibroblast activation protein plays an essential role in remodeling collagen-rich matrices in the context of fibrosis and cancer. We observed that FAP-null mice have increased weight compared to wild-type controls, and so investigated the role of FAP in regulating diet-induced obesity. Using genetically engineered mouse models and in-vitro cell-derived matrices, we demonstrate that FAP expression by pre-adipocytes restrains adipogenic differentiation. We further show that FAP-mediated matrix remodeling alters lipid metabolism in part by regulating mTOR signaling. The impact of FAP on adipogenic differentiation and mTOR signaling together confers resistance to diet-induced obesity. The critical role of ECM remodeling in regulating obesity offers new potential targets for therapy.

中文翻译：

---

成纤维细胞活化蛋白抑制脂肪形成分化并调节基质介导的 mTOR 信号传导。

肥胖是多种疾病的危险因素，包括糖尿病、心血管疾病和癌症。在肥胖的脂肪组织中，多种因素有助于创造一个促进疾病的环境，包括代谢功能障碍、炎症和纤维化。最近的证据表明纤维化反应，特别是细胞外基质重塑，在肥胖的发病机制中发挥着重要作用。在纤维化和癌症的背景下，成纤维细胞活化蛋白在重塑富含胶原蛋白的基质中起着至关重要的作用。我们观察到与野生型对照相比，FAP 缺失小鼠体重增加，因此研究了 FAP 在调节饮食诱导的肥胖中的作用。使用基因工程小鼠模型和体外细胞衍生基质，我们证明前脂肪细胞的 FAP 表达抑制脂肪形成分化。我们进一步表明，FAP 介导的基质重塑部分通过调节 mTOR 信号来改变脂质代谢。FAP 对脂肪形成分化和 mTOR 信号的影响共同赋予了对饮食诱导的肥胖的抵抗力。ECM 重塑在调节肥胖中的关键作用为治疗提供了新的潜在目标。