The brown fat–enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis

Abstract

Brown fat activates uncoupled respiration in response to cold temperature and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here we show that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat–enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD).

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Figure 1: Identification of Nrg4 as a brown fat–enriched secreted protein.
Figure 2: Nrg4 binds to hepatocytes and is dispensable for defense against cold.
Figure 3: Nrg4 deficiency exacerbates diet-induced hepatic steatosis.
Figure 4: Nrg4 cell-autonomously attenuates de novo lipogenesis in hepatocytes.
Figure 5: Nrg4 expression in adipose tissue is reduced in mouse and human obesity.
Figure 6: Transgenic expression of Nrg4 alleviates diet-induced fatty liver through attenuating lipogenesis.

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Acknowledgements

We thank P. Dempsey (University of Colorado) for ErbB4-Min6 cells, Y. Yarden (Weizmann Institute of Science) for ErbB expression plasmids, D. Leahy (Johns Hopkins University) for expression constructs for ErbB3 and ErbB4 extracellular domains, D. Threadgill (Texas A&M University) for Erbb3flox/flox mice and A. Saltiel for discussions. We are grateful to Q. Yu and L. Wang for technical support, the lab members for discussion, and the staff at the University of Michigan Transgenic Animal Model Core and the metabolic phenotyping core supported by Michigan Diabetes Research and Training Center (DK020572) and Nutrition Obesity Research Center (DK089503). This work was supported by the US National Institutes of Health (DK077086 and DK095151, J.D.L.; DK097608, X.S.) and a grant from Novo Nordisk. S.L. and G.-X.W. were supported by Scientist Development Grant and Predoctoral Fellowship, respectively, from the American Heart Association.

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J.D.L., G.-X.W. and X.-Y.Z. conceived the project and designed research. G.-X.W., X.-Y.Z., Z. Chen, Z. Cozacov, S.L. and Z.-X.M. performed metabolic and molecular studies; M.K., A.D. and M.B. performed human studies. D.Z., A.L.O. and X.S. performed lipid profile analysis. G.-X.W. and J.D.L. wrote the manuscript.

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Correspondence to Jiandie D Lin.

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This work was partially supported by a research agreement with Novo Nordisk.

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Wang, GX., Zhao, XY., Meng, ZX. et al. The brown fat–enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med 20, 1436–1443 (2014). https://doi.org/10.1038/nm.3713

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