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 5

MSTN ablation in BAT shows signatures of mitochondrial dysfunction and inflammation.

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MSTN ablation in BAT shows signatures of mitochondrial dysfunction and i...
(A) PCA plot of the BAT samples from the BKO and Flox groups. (B) Heatmap plot comparing 414 upregulated genes and 202 downregulated genes between BKO and Flox groups. (C) Enriched KEGG pathways for downregulated genes. (D) Enriched KEGG pathways for upregulated genes. (E) Relative mRNA expression of inflammatory genes (n = 6). (F) F4/80 staining of BAT. Scale bars: 20 μm. (G) Relative mRNA expression of inflammatory genes in macrophages cocultured with BAT from BKO or Flox mice (n = 5). (H) Western blot analysis of KLF4 in BAT (n = 3). (I) Relative mRNA expression of Klf4 in BAT (n = 6). (J) Schematic model of the downstream pathway of MSTN. (K) Western blot analysis of SMAD2/3 and the non-SMAD pathway in BAT from BKO and Flox mice (n = 3). t, total. (L and M) Western blot analysis of KLF4 in primary brown adipocytes treated with PBS and a SMAD2/3 or p38 inhibitor (n = 3). (N) Western blot analysis of KLF4 in primary brown adipocytes from Flox and BKO mice. In the BKO plus p38 agonist group, primary brown adipocytes were treated with 1 μM dehydrocorydaline (n = 3). (O) Western blot analysis of KLF4 in primary brown adipocytes treated with PBS, rMSTN, or rMSTN plus inhibitors. In the rMSTN plus inhibitors group, primary brown adipocytes were treated with a SMAD2/3 and p38 inhibitor (n = 3). All results are shown as the mean ± SEM. **P < 0.01 and ***P < 0.001, by 2-tailed Student t test.