State Key Laboratory of Genetic Engineering and School of Life Sciences, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Fudan University, Shanghai, China.
Department of Sports Medicine and Arthroscopy Surgery, Huashan Hospital, Fudan University, Shanghai, China.
J Clin Invest. 2024 Jun 18;134(16):e178303. doi: 10.1172/JCI178303.
Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTNΔUCP1) and found that the mice gained more weight than did controls when fed a high-fat diet, with progressive hepatosteatosis and impaired skeletal muscle activity. RNA-Seq analysis indicated signatures of mitochondrial dysfunction and inflammation in the MSTN-ablated BAT. Further studies demonstrated that Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, whereas fibroblast growth factor 21 (FGF21) contributed to the microenvironment communication between adipocytes and macrophages induced by the loss of MSTN. Moreover, the MSTN/SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. In summary, our findings suggest that brown adipocyte-derived MSTN regulated BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.
肌肉生长抑制素 (MSTN) 长期以来一直被认为是肌肉质量的关键调节因子。最近，人们对其在代谢中的作用越来越感兴趣。在我们的研究中，我们专门敲除了棕色脂肪组织 (BAT) 中的 MSTN（MSTNΔUCP1），发现与对照组相比，高脂饮食喂养的 MSTN 缺失小鼠体重增加更多，出现进行性肝脂肪变性和骨骼肌活动受损。RNA-Seq 分析表明 MSTN 缺失的 BAT 存在线粒体功能障碍和炎症的特征。进一步的研究表明，Krüppel 样因子 4 (KLF4) 是导致观察到的代谢表型的原因，而成纤维细胞生长因子 21 (FGF21) 则有助于由 MSTN 缺失引起的脂肪细胞和巨噬细胞之间的微环境通讯。此外，MSTN/SMAD2/3-p38 信号通路介导了脂肪细胞中 KLF4 和 FGF21 的表达。总之，我们的研究结果表明，棕色脂肪细胞源性 MSTN 通过自分泌和旁分泌作用调节脂肪细胞或巨噬细胞的 BAT 产热，最终调节全身能量稳态。
