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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
References
Finucane, M. M. et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 377, 557–567 (2011).
Brown, M. S. & Goldstein, J. L. Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic. J. Clin. Invest. 72, 743–747 (1983).
Kuriyama, H. et al. Compensatory increase in fatty acid synthesis in adipose tissue of mice with conditional deficiency of SCAP in liver. Cell Metab. 1, 41–51 (2005).
Stefan, N. & Haring, H. U. The role of hepatokines in metabolism. Nat. Rev. Endocrinol. 9, 144–152 (2013).
Meex, R. C. et al. Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism. Cell Metab. 22, 1078–1089 (2015).
Gong, Y. et al. Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell Metab. 3, 15–24 (2006).
Brown, M. S. & Goldstein, J. L. Cholesterol feedback: from Schoenheimer’s bottle to Scap’s MELADL. J. Lipid Res. 50, S15–S27 (2009).
Sun, L. P., Seemann, J., Goldstein, J. L. & Brown, M. S. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins. Proc. Natl Acad. Sci. USA 104, 6519–6526 (2007).
Horton, J. D. Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis. Biochem. Soc. Trans. 30, 1091–1095 (2002).
Hua, X. et al. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc. Natl Acad. Sci. USA 90, 11603–11607 (1993).
Miserez, A. R., Cao, G., Probst, L. C. & Hobbs, H. H. Structure of the human gene encoding sterol regulatory element binding protein 2 (SREBF2). Genomics 40, 31–40 (1997).
Liu, T. F. et al. Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis. Cell Metab. 16, 213–225 (2012).
Lee, J. N., Song, B., DeBose-Boyd, R. A. & Ye, J. Sterol-regulated degradation of Insig-1 mediated by the membrane-bound ubiquitin ligase gp78. J. Biol. Chem. 281, 39308–39315 (2006).
Song, B. L., Sever, N. & DeBose-Boyd, R. A. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol. Cell 19, 829–840 (2005).
Meex, R. C. R. & Watt, M. J. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat. Rev. Endocrinol. 13, 509–520 (2017).
Azimifar, S. B., Nagaraj, N., Cox, J. & Mann, M. Cell-type-resolved quantitative proteomics of murine liver. Cell Metab. 20, 1076–1087 (2014).
Rose, A. A. et al. ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties. PLoS ONE 5, e12093 (2010).
Yu, B., Sondag, G. R., Malcuit, C., Kim, M. H. & Safadi, F. F. Macrophage-associated osteoactivin/GPNMB mediates mesenchymal stem cell survival, proliferation, and migration via a CD44-dependent mechanism. J. Cell Biochem. 117, 1511–1521 (2016).
Takashima, M., Ogawa, W., Emi, A. & Kasuga, M. Regulation of SREBP1c expression by mTOR signaling in hepatocytes. Kobe J. Med. Sci. 55, E45–E52 (2009).
Yecies, J. L. et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 14, 21–32 (2011).
Duncan, R. E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E. & Sul, H. S. Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 27, 79–101 (2007).
Feng, B. et al. Clodronate liposomes improve metabolic profile and reduce visceral adipose macrophage content in diet-induced obese mice. PLoS ONE 6, e24358 (2011).
Gao, G. P. et al. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl Acad. Sci. USA 99, 11854–11859 (2002).
Hong, J. et al. Genetic susceptibility, birth weight and obesity risk in young Chinese. Int. J. Obes. 37, 673–677 (2013).
Rao, R. R. et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279–1291 (2014).
Kodama, K. et al. Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes. Proc. Natl Acad. Sci. USA 109, 7049–7054 (2012).
Weiss, L. et al. Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with a specific monoclonal antibody. Proc. Natl Acad. Sci. USA 97, 285–290 (2000).
Kodama, K., Toda, K., Morinaga, S., Yamada, S. & Butte, A. J. Anti-CD44 antibody treatment lowers hyperglycemia and improves insulin resistance, adipose inflammation, and hepatic steatosis in diet-induced obese mice. Diabetes 64, 867–875 (2015).
Dodd, G. T. et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160, 88–104 (2015).
Ruan, H. B. et al. O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell 159, 306–317 (2014).
Zhu, Y. et al. Connexin 43 mediates white adipose tissue beiging by facilitating the propagation of sympathetic neuronal signals. Cell Metab. 24, 420–433 (2016).
Zhou, Q. L. et al. Membrane Trafficking Protein CDP138 Regulates Fat Browning and Insulin Sensitivity through Controlling Catecholamine Release. Mol. Cell. Biol. 38, e00153-17 (2018).
Kitamura, T. et al. Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. Mol. Cell. Biol. 19, 6286–6296 (1999).
Dickson, L. M., Gandhi, S., Layden, B. T., Cohen, R. N. & Wicksteed, B. Protein kinase A induces UCP1 expression in specific adipose depots to increase energy expenditure and improve metabolic health. Am. J Physiol. Regul. Integr. Comp. Physiol. 311, R79–R88 (2016).
Fredriksson, J. M. et al. Analysis of inhibition by H89 of UCP1 gene expression and thermogenesis indicates protein kinase A mediation of beta(3)-adrenergic signalling rather than beta(3)-adrenoceptor antagonism by H89. Biochim. Biophys. Acta 1538, 206–217 (2001).
Anderson, M. G. et al. Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nat. Genet. 30, 81–85 (2002).
Ripoll, V. M. et al. Microphthalmia transcription factor regulates the expression of the novel osteoclast factor GPNMB. Gene 413, 32–41 (2008).
Abdelmagid, S. M. et al. Osteoactivin acts as downstream mediator of BMP-2 effects on osteoblast function. J. Cell. Physiol. 210, 26–37 (2007).
Schwarzbich, M. A. et al. The immune inhibitory receptor osteoactivin is upregulated in monocyte-derived dendritic cells by BCR-ABL tyrosine kinase inhibitors. Cancer Immunol. Immunother. 61, 193–202 (2012).
Choi, M. S. et al. High-fat diet decreases energy expenditure and expression of genes controlling lipid metabolism, mitochondrial function and skeletal system development in the adipose tissue, along with increased expression of extracellular matrix remodelling- and inflammation-related genes. Br. J. Nutr. 113, 867–877 (2015).
Kuan, C. T. et al. Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clin. Cancer Res. 12, 1970–1982 (2006).
Okamoto, I. et al. Seven novel and stable translocations associated with oncogenic gene expression in malignant melanoma. Neoplasia 7, 303–311 (2005).
Rose, A. A. et al. Osteoactivin promotes breast cancer metastasis to bone. Mol. Cancer Res. 5, 1001–1014 (2007).
Zhou, L. T. et al. Gpnmb/osteoactivin, an attractive target in cancer immunotherapy. Neoplasma 59, 1–5 (2012).
Choi, C. H. J. & Cohen, P. Adipose crosstalk with other cell types in health and disease. Exp. Cell Res. 360, 6–11 (2017).
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
Maeda, K. et al. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose most abundant Gene transcript 1). Biochem. Biophys. Res. Commun. 221, 286–289 (1996).
Long, J. Z. et al. The secreted enzyme PM20D1 regulates lipidated amino acid uncouplers of mitochondria. Cell 166, 424–435 (2016).
Feve, B., Bastard, C., Fellahi, S., Bastard, J. P. & Capeau, J. New adipokines. Ann. Endocrinol. (Paris) 77, 49–56 (2016).
Bostrom, P. et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).
Hondares, E. et al. Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 11, 206–212 (2010).
Fisher, F. M. et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271–281 (2012).
Xie, T. & Leung, P. S. Fibroblast growth factor 21: a regulator of metabolic disease and health span. Am. J. Physiol. Endocrinol. Metab. 313, E292–E302 (2017).
Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).
Liao, Y. C. et al. The non-canonical NF-kappa B pathway promotes NPC2 expression and regulates intracellular cholesterol trafficking. Sci. China Life Sci. 61, 1222–1232 (2018).
Ferre, P., Leturque, A., Burnol, A. F., Penicaud, L. & Girard, J. A method to quantify glucose utilization in vivo in skeletal muscle and white adipose tissue of the anaesthetized rat. Biochem. J. 228, 103–110 (1985).
Liu, R. et al. Rare loss-of-function variants in NPC1 predispose to human obesity. Diabetes 66, 935–947 (2017).
Wang, J. et al. Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat. Cell Biol. 15, 1455–1463 (2013).
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
Authors and Affiliations
Contributions
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.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information
Supplementary Figs. 1–15 and Supplementary Tables 1–3
Rights and permissions
About this article
Cite this article
Gong, XM., Li, YF., Luo, J. et al. Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance. Nat Metab 1, 570–583 (2019). https://doi.org/10.1038/s42255-019-0065-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s42255-019-0065-4
This article is cited by
-
IGF2BP3-mediated enhanced stability of MYLK represses MSC adipogenesis and alleviates obesity and insulin resistance in HFD mice
Cellular and Molecular Life Sciences (2024)
-
Thermogenic adipocyte-derived zinc promotes sympathetic innervation in male mice
Nature Metabolism (2023)
-
Anti-inflammatory role of Gpnmb in adipose tissue of mice
Scientific Reports (2021)
-
AMPK-mediated phosphorylation enhances the auto-inhibition of TBC1D17 to promote Rab5-dependent glucose uptake
Cell Death & Differentiation (2021)
-
GPNMB: expanding the code for liver–fat communication
Nature Metabolism (2019)