Metabolism in mammals is regulated by complex interplay among different organs. Fatty acid synthesis is increased in white adipose tissue (WAT) when it is inhibited in the liver. Here we identify glycoprotein non-metastatic melanoma protein B (Gpnmb) as one liver–WAT cross-talk factor involved in lipogenesis. Inhibition of the hepatic sterol regulatory element-binding protein pathway leads to increased transcription of Gpnmb and promotes processing of the membrane protein to a secreted form. Gpnmb stimulates lipogenesis in WAT and exacerbates diet-induced obesity and insulin resistance. In humans, Gpnmb is tightly associated with body mass index and is a strong risk factor for obesity. Gpnmb inhibition by a neutralizing antibody or liver-specific knockdown improves metabolic parameters, including weight gain reduction and increased insulin sensitivity, probably by promoting the beiging of WAT. These results suggest that Gpnmb is a liver-secreted factor regulating lipogenesis in WAT, and that Gpnmb inhibition may provide a therapeutic strategy in obesity and diabetes.
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The microarray dataset described in the paper has been deposited in the Gene Expression Omnibus database with accession number GSE129283. The data that support the findings of this study are available from the corresponding author upon reasonable request.
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We thank H.-H. Miao, Y.-X. Qu, J. Xu, D. Liang, B.-Y. Xiang and Y.Y. Liu for technical assistance, Y.-K. Sun for human sample collection and Y. He for statistical analysis. This work was supported by grants from the National Natural Science Foundation (China; Nos. 31430044, 31690102, 91857000 and 81522011), Ministry of Science and Technology (China; No. 2016YFA0500100), the Science and Technology Department of Hubei Province (No. 2016CFA012) and the 111 Project of the Ministry of Education of China (No. B16036).
The authors declare no competing interests.
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Nature Metabolism (2019)