Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communications

Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been an 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 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-ablation BAT. Further studies demonstrated that the the Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, while 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 adipocytes-derived MSTN regulates BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.