Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communication
Hui Wang, … , Tiemin Liu, Xingxing Kong
Hui Wang, … , Tiemin Liu, Xingxing Kong
Published June 18, 2024
Citation Information: J Clin Invest. 2024;134(16):e178303. https://doi.org/10.1172/JCI178303.
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Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communication

Abstract

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.

Authors

Hui Wang, Shanshan Guo, Huanqing Gao, Jiyang Ding, Hongyun Li, Xingyu Kong, Shuang Zhang, Muyang He, Yonghao Feng, Wei Wu, Kexin Xu, Yuxuan Chen, Hanyin Zhang, Tiemin Liu, Xingxing Kong

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Figure 1

Mice with BAT-specific MSTN KO are prone to DIO.

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Mice with BAT-specific MSTN KO are prone to DIO. (A) Western blot analys...
(A) Western blot analysis of the expression of MSTN in BAT from DIO mice (n = 3). (B) mRNA expression of Mstn in BAT from DIO mice (n = 5). Con, control. (C) Western blot analysis of the expression of MSTN in BAT from male BKO and Flox mice on a 12-week HFD (n = 3). (D) mRNA expression of Mstn in BAT, GAS, and iWAT from male BKO and Flox mice on a 12-week HFD (n = 7). (E) Body weight of male BKO and Flox mice on a HFD (n = 7–10). (F) Body composition of male BKO and Flox mice on a HFD (n = 7). (G) Weight of BAT, iWAT, epididymal WAT (eWAT), and GAS tissue from male BKO and Flox mice on a 12-week HFD (n = 7). (H) Images showing the morphology of BAT, iWAT, and eWAT. (I) H&E staining of BAT, iWAT of male BKO and Flox mice on a 12-week HFD. Scale bars: 20 μm. (J–M) GTTs and ITTs for male BKO and Flox mice (n = 6–7). (N–Q) The OCR (VO2), carbon dioxide production (VCO2), energy expenditure, and RER of male BKO and Flox mice on a 12-week HFD (n = 6–7). (R) Body temperature of male BKO and Flox mice during cold challenges (n = 7). All results are shown as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test.