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Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance

Abstract

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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Data availability

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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Acknowledgements

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).

Author information

B.-L.S. conceived the project. X.-M.G., Y.-F.L., G.N., J.-Q.W., J.W., B.-L.L., W.Q. and B.-L.S. designed the experiments. X.-M.G., Y.-F.L., J.-Q.W., T.X., J.W., C.X. and J.H. performed the experiments. X.-M.G., Y.-F.L., J.L. and B.-L.S. analyzed the data. J.-Q.W. provided and analyzed the human serum samples. X.-M.G., Y.-F.L., J.L., W.Q. and B.-L.S. wrote the paper, with input from others.

Correspondence to Wei Qi or Bao-Liang Song.

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Further reading

Fig. 1: Compensatory elevation of lipogenic genes in WAT from L-Scap−/− or L-gp78−/− mice.
Fig. 2: Gpnmb is proteolytically cleaved and secreted from the liver, and adenovirus-mediated expression of Gpnmb drives fatty-acid-synthesis gene expression in WAT.
Fig. 3: Gpnmb-ECD stimulates the AKT signalling pathway via CD44 in adipocytes.
Fig. 4: Gpnmb increases lipogenesis in WAT.
Fig. 5: Gpnmb promotes diet-induced obesity and insulin resistance.
Fig. 6: Effects of Gpnmb neutralization on DIO mice.