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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Research Article Endocrinology

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 7

FGF21 contributes to the inflammatory phenotypes induced by MSTN ablation.

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FGF21 contributes to the inflammatory phenotypes induced by MSTN ablatio...
(A) Western blot analysis of FGF21 in BAT from BKO and Flox mice on a 12-week HFD (n = 3). (B) Relative mRNA expression of Fgf21 in BAT (n = 6). (C) Relative mRNA expression of Fgf21 in BAT SVFs and mature adipocytes from BKO and Flox mice on a 12-week HFD (n = 5). (D) Western blot analysis of FGF21 in primary brown adipocytes of control and MSTN-knockdown groups (n = 3). (E) Western blot analysis of FGF21 in primary brown adipocytes treated with PBS or p38 inhibitor (n = 3). (F) Western blot analysis of FGF21 in primary brown adipocytes from Flox or BKO mice. In the BKO+p38 agonist group, primary brown adipocytes were treated with 1 μM dehydrocorydaline (n = 3). (G) Western blot analysis of FGF21 in primary brown adipocytes treated with a SMAD2/3 inhibitor (n = 3). (H) Western blot analysis of FGF21 in primary brown adipocytes treated with PBS, rMSTN, or rMSTN plus inhibitors (n = 3). In the rMSTN plus inhibitors group, primary brown adipocytes were treated with SMAD2/3 and p38 inhibitor. (I and J) Relative mRNA expression of inflammatory genes (I) and NF-κB signaling pathway–related genes (J) in macrophages cocultured with BAT from Flox and BKO mice. In the BKO+rFGF21 group, macrophages were additionally treated with 100 nM rFGF21 (n = 4). (K) Relative mRNA expression of inflammatory genes in BAT from Flox, BKO+GFP, and BKO+FGF21 mice (n = 3–4). (L) Working model. All results are shown as the mean ± SEM. **P < 0.01 and ***P < 0.001, compared with the Flox group; #P < 0.05, ##P < 0.01, and ###P < 0.001, compared with the BKO group. A 2-tailed Student t test was used for 2-group statistical analyses, and 1-way ANOVA followed by Bonferroni’s post test was used for 3-group statistical analyses.