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


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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  1. 1

    Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    CAS  PubMed  Google Scholar 

  2. 2

    Kozak, L.P. & Harper, M.E. Mitochondrial uncoupling proteins in energy expenditure. Annu. Rev. Nutr. 20, 339–363 (2000).

    CAS  PubMed  Google Scholar 

  3. 3

    Lowell, B.B. et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Yoneshiro, T. et al. Recruited brown adipose tissue as an antiobesity agent in humans. J. Clin. Invest. 123, 3404–3408 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).

    CAS  PubMed  Google Scholar 

  6. 6

    van der Lans, A.A. et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J. Clin. Invest. 123, 3395–3403 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Nedergaard, J., Bengtsson, T. & Cannon, B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007).

    CAS  PubMed  Google Scholar 

  8. 8

    Cypess, A.M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    van Marken Lichtenbelt, W.D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).

    CAS  PubMed  Google Scholar 

  10. 10

    Virtanen, K.A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).

    CAS  PubMed  Google Scholar 

  11. 11

    Enerbäck, S. Human brown adipose tissue. Cell Metab. 11, 248–252 (2010).

    PubMed  Google Scholar 

  12. 12

    Nedergaard, J. & Cannon, B. The changed metabolic world with human brown adipose tissue: therapeutic visions. Cell Metab. 11, 268–272 (2010).

    CAS  PubMed  Google Scholar 

  13. 13

    Petrovic, N. et al. Chronic peroxisome proliferator-activated receptor γ (PPARγ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J. Biol. Chem. 285, 7153–7164 (2010).

    CAS  PubMed  Google Scholar 

  14. 14

    Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Cypess, A.M. et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat. Med. 19, 635–639 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Jespersen, N.Z. et al. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab. 17, 798–805 (2013).

    CAS  PubMed  Google Scholar 

  17. 17

    Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Enerbäck, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997).

    PubMed  Google Scholar 

  19. 19

    Feldmann, H.M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 9, 203–209 (2009).

    CAS  PubMed  Google Scholar 

  20. 20

    Liu, X. et al. Paradoxical resistance to diet-induced obesity in UCP1-deficient mice. J. Clin. Invest. 111, 399–407 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Kadowaki, T. et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Invest. 116, 1784–1792 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Trujillo, M.E. & Scherer, P.E. Adipose tissue-derived factors: impact on health and disease. Endocr. Rev. 27, 762–778 (2006).

    CAS  PubMed  Google Scholar 

  23. 23

    Waki, H. & Tontonoz, P. Endocrine functions of adipose tissue. Annu. Rev. Pathol. 2, 31–56 (2007).

    CAS  PubMed  Google Scholar 

  24. 24

    Angelin, B., Larsson, T.E. & Rudling, M. Circulating fibroblast growth factors as metabolic regulators—a critical appraisal. Cell Metab. 16, 693–705 (2012).

    CAS  PubMed  Google Scholar 

  25. 25

    Potthoff, M.J., Kliewer, S.A. & Mangelsdorf, D.J. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 26, 312–324 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Pedersen, B.K. & Febbraio, M.A. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 457–465 (2012).

    CAS  PubMed  Google Scholar 

  27. 27

    Kim, K.H. et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19, 83–92 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Karsenty, G. & Ferron, M. The contribution of bone to whole-organism physiology. Nature 481, 314–320 (2012).

    CAS  PubMed  Google Scholar 

  29. 29

    Schneider, M.R. & Wolf, E. The epidermal growth factor receptor ligands at a glance. J. Cell. Physiol. 218, 460–466 (2009).

    CAS  PubMed  Google Scholar 

  30. 30

    Holbro, T. & Hynes, N.E. ErbB receptors: directing key signaling networks throughout life. Annu. Rev. Pharmacol. Toxicol. 44, 195–217 (2004).

    CAS  PubMed  Google Scholar 

  31. 31

    Bublil, E.M. & Yarden, Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr. Opin. Cell Biol. 19, 124–134 (2007).

    CAS  PubMed  Google Scholar 

  32. 32

    Chen, Y. et al. SPD—a web-based secreted protein database. Nucleic Acids Res. 33, D169–D173 (2005).

    CAS  PubMed  Google Scholar 

  33. 33

    Odiete, O., Hill, M.F. & Sawyer, D.B. Neuregulin in cardiovascular development and disease. Circ. Res. 111, 1376–1385 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Hayes, N.V., Newsam, R.J., Baines, A.J. & Gullick, W.J. Characterization of the cell membrane-associated products of the neuregulin 4 gene. Oncogene 27, 715–720 (2008).

    CAS  PubMed  Google Scholar 

  35. 35

    Harari, D. et al. Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene 18, 2681–2689 (1999).

    CAS  PubMed  Google Scholar 

  36. 36

    Müller, H., Dai, G. & Soares, M.J. Placental lactogen-I (PL-I) target tissues identified with an alkaline phosphatase-PL-I fusion protein. J. Histochem. Cytochem. 46, 737–743 (1998).

    PubMed  Google Scholar 

  37. 37

    Horton, J.D., Goldstein, J.L. & Brown, M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Carver, R.S., Stevenson, M.C., Scheving, L.A. & Russell, W.E. Diverse expression of ErbB receptor proteins during rat liver development and regeneration. Gastroenterology 123, 2017–2027 (2002).

    CAS  PubMed  Google Scholar 

  39. 39

    Olayioye, M.A., Beuvink, I., Horsch, K., Daly, J.M. & Hynes, N.E. ErbB receptor–induced activation of stat transcription factors is mediated by Src tyrosine kinases. J. Biol. Chem. 274, 17209–17218 (1999).

    CAS  PubMed  Google Scholar 

  40. 40

    Jones, F.E., Welte, T., Fu, X.Y. & Stern, D.F. ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation. J. Cell Biol. 147, 77–88 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Repa, J.J. et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev. 14, 2819–2830 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Schultz, J.R. et al. Role of LXRs in control of lipogenesis. Genes Dev. 14, 2831–2838 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Stöcklin, E., Wissler, M., Gouilleux, F. & Groner, B. Functional interactions between Stat5 and the glucocorticoid receptor. Nature 383, 726–728 (1996).

    PubMed  Google Scholar 

  44. 44

    Gregor, M.F. & Hotamisligil, G.S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011).

    CAS  PubMed  Google Scholar 

  45. 45

    Odegaard, J.I. & Chawla, A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 339, 172–177 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Osborn, O. & Olefsky, J.M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363–374 (2012).

    CAS  Google Scholar 

  47. 47

    Hotamisligil, G.S., Shargill, N.S. & Spiegelman, B.M. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    CAS  Google Scholar 

  48. 48

    Kohjima, M. et al. SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int. J. Mol. Med. 21, 507–511 (2008).

    CAS  PubMed  Google Scholar 

  49. 49

    Shimomura, I., Bashmakov, Y. & Horton, J.D. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J. Biol. Chem. 274, 30028–30032 (1999).

    CAS  PubMed  Google Scholar 

  50. 50

    Knebel, B. et al. Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass. PLoS ONE 7, e31812 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Shimano, H. et al. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J. Clin. Invest. 99, 846–854 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Tang, J.J. et al. Inhibition of SREBP by a small molecule, betulin, improves hyperlipidemia and insulin resistance and reduces atherosclerotic plaques. Cell Metab. 13, 44–56 (2011).

    CAS  PubMed  Google Scholar 

  53. 53

    Moon, Y.A. et al. The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals. Cell Metab. 15, 240–246 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Rosell, M. et al. Brown and white adipose tissues. Intrinsic differences in gene expression and response to cold exposure in mice. Am. J. Physiol. Endocrinol. Metab. 306, E945–E964 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Klein, J., Fasshauer, M., Klein, H.H., Benito, M. & Kahn, C.R. Novel adipocyte lines from brown fat: a model system for the study of differentiation, energy metabolism, and insulin action. Bioessays 24, 382–388 (2002).

    CAS  PubMed  Google Scholar 

  56. 56

    Lin, J. & Linzer, D.I. Induction of megakaryocyte differentiation by a novel pregnancy-specific hormone. J. Biol. Chem. 274, 21485–21489 (1999).

    CAS  PubMed  Google Scholar 

  57. 57

    Leahy, D.J., Dann, C.E. III, Longo, P., Perman, B. & Ramyar, K.X. A mammalian expression vector for expression and purification of secreted proteins for structural studies. Protein Expr. Purif. 20, 500–506 (2000).

    CAS  PubMed  Google Scholar 

  58. 58

    Lin, J. et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119, 121–135 (2004).

    CAS  PubMed  Google Scholar 

  59. 59

    Li, S. et al. Genome-wide coactivation analysis of PGC-1alpha identifies BAF60a as a regulator of hepatic lipid metabolism. Cell Metab. 8, 105–117 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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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).

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