The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation

Abstract

Thermogenesis is an important contributor to whole-body energy expenditure and metabolic homeostasis. Although circulating factors that promote energy expenditure are known, endocrine molecules that suppress energy expenditure have remained largely elusive. Here we found that Tsukushi (TSK) is a liver-enriched secreted factor that is highly inducible in response to increased energy expenditure. Hepatic Tsk expression and plasma TSK levels were elevated in obesity. In mice, TSK deficiency increased sympathetic innervation and norepinephrine release in adipose tissue, leading to enhanced adrenergic signalling and thermogenesis, attenuation of brown fat whitening, and protection from diet-induced obesity. Our data reveal TSK as part of a negative feedback mechanism that gates thermogenic energy expenditure and highlights TSK as a potential target for therapeutic intervention in metabolic disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: TSK is a hepatokine responsive to increased energy expenditure.
Fig. 2: TSK facilitates diet-induced obesity and brown fat whitening.
Fig. 3: TSK ablation relieves a brake on sympathetic action in adipose tissue.
Fig. 4: Hepatic Tsk inactivation ameliorates HFD-induced insulin resistance.
Fig. 5: TSK regulates brown fat thermogenesis through sympathetic innervation.
Fig. 6: Role of TSK as a hepatokine checkpoint for thermogenesis and energy balance.

Data availability

The microarray dataset described in the paper has been deposited in the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/) with accession number GSE114361. All other data are available from the corresponding author on reasonable request.

References

  1. 1.

    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  Article  Google Scholar 

  2. 2.

    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  Article  Google Scholar 

  3. 3.

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

    CAS  PubMed  Article  Google Scholar 

  4. 4.

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

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Flier, J. S. & Maratos-Flier, E. Leptin’s physiologic role: does the emperor of energy balance have no clothes? Cell. Metab. 26, 24–26 (2017).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Friedman, J. 20 years of leptin: leptin at 20: an overview. J. Endocrinol. 223, T1–T8 (2014).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Staiger, H., Keuper, M., Berti, L., Hrabe de Angelis, M. & Haring, H. U. Fibroblast growth factor 21 - metabolic role in mice and men. Endocr. Rev. 38, 468–488 (2017).

    PubMed  Article  Google Scholar 

  8. 8.

    Stefan, N. & Haring, H. U. The role of hepatokines in metabolism. Nat. Rev. Endocrinol. 9, 144–152 (2013).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Yanagi, S., Sato, T., Kangawa, K. & Nakazato, M. The homeostatic force of ghrelin. Cell. Metab. 27, 786–804 (2018).

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Crewe, C., An, Y. A. & Scherer, P. E. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J. Clin. Invest. 127, 74–82 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Martinez-Santibanez, G. & Lumeng, C. N. Macrophages and the regulation of adipose tissue remodeling. Annu. Rev. Nutr. 34, 57–76 (2014).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Reilly, S. M. & Saltiel, A. R. Adapting to obesity with adipose tissue inflammation. Nat. Rev. Endocrinol. 13, 633–643 (2017).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

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

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Townsend, K. L. & Tseng, Y. H. Brown fat fuel utilization and thermogenesis. Trends Endocrinol. Metab. 25, 168–177 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Wu, J., Cohen, P. & Spiegelman, B. M. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 27, 234–250 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Ikeda, K. et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat. Med. 23, 1454–1465 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Ikeda, K., Maretich, P. & Kajimura, S. The common and distinct features of brown and beige adipocytes. Trends Endocrinol. Metab. 29, 191–200 (2018).

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Kazak, L. et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163, 643–655 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Chen, Z. et al. Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders. Mol. Metab. 6, 863–872 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Guo, L. et al. Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J. Clin. Invest. 127, 4449–4461 (2017).

  23. 23.

    Wang, G. X. et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat. Med. 20, 1436–1443 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    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  Article  Google Scholar 

  25. 25.

    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  Article  Google Scholar 

  26. 26.

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

    CAS  PubMed  Article  Google Scholar 

  27. 27.

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

    PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Cho, K. W., Zhou, Y., Sheng, L. & Rui, L. Lipocalin-13 regulates glucose metabolism by both insulin-dependent and insulin-independent mechanisms. Mol. Cell. Biol. 31, 450–457 (2011).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Meex, R. C. et al. Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism. Cell. Metab. 22, 1078–1089 (2015).

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Ohba, K. et al. Desensitization and incomplete recovery of hepatic target genes after chronic thyroid hormone treatment and withdrawal in male adult mice. Endocrinology 157, 1660–1672 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Hossain, M. et al. The combinatorial guidance activities of draxin and Tsukushi are essential for forebrain commissure formation. Dev. Biol. 374, 58–70 (2013).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Ito, A. et al. Tsukushi is required for anterior commissure formation in mouse brain. Biochem. Biophys. Res. Commun. 402, 813–818 (2010).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Ohta, K. et al. Tsukushi functions as an organizer inducer by inhibition of BMP activity in cooperation with chordin. Dev. Cell. 7, 347–358 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    de Jesus, L. A. et al. The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J. Clin. Invest. 108, 1379–1385 (2001).

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Zhao, X. Y. et al. Long noncoding RNA licensing of obesity-linked hepatic lipogenesis and NAFLD pathogenesis. Nat. Commun. 9, 2986 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Bartness, T. J., Liu, Y., Shrestha, Y. B. & Ryu, V. Neural innervation of white adipose tissue and the control of lipolysis. Front. Neuroendocrinol. 35, 473–493 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Morrison, S. F. & Madden, C. J. Central nervous system regulation of brown adipose tissue. Compr. Physiol. 4, 1677–1713 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Zeng, W. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163, 84–94 (2015).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Bachman, E. S. et al. betaAR signaling required for diet-induced thermogenesis and obesity resistance. Science 297, 843–845 (2002).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Bray, G. A. & York, D. A. The MONA LISA hypothesis in the time of leptin. Recent Prog. Horm. Res. 53, 95–117 (1998); discussion 117–118.

    CAS  PubMed  Google Scholar 

  41. 41.

    Cao, Y., Wang, H., Wang, Q., Han, X. & Zeng, W. Three-dimensional volume fluorescence-imaging of vascular plasticity in adipose tissues. Mol. Metab. 14, 71–81 (2018).

  42. 42.

    Chi, J. et al. Three-dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell. Metab. 27, 226–236 e223 (2018).

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Jiang, H., Ding, X., Cao, Y., Wang, H. & Zeng, W. Dense intra-adipose sympathetic arborizations are essential for cold-induced beiging of mouse white adipose tissue. Cell. Metab. 26, 686–692 e683 (2017).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Camell, C. D. et al. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550, 119–123 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Pirzgalska, R. M. et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat. Med. 23, 1309–1318 (2017).

    CAS  PubMed  Google Scholar 

  46. 46.

    Ran, F. A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Zhao, X. Y., Li, S., Wang, G. X., Yu, Q. & Lin, J. D. A long noncoding RNA transcriptional regulatory circuit drives thermogenic adipocyte differentiation. Mol. Cell 55, 372–382 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    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  Article  Google Scholar 

  49. 49.

    Muller, 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).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

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

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants (nos. DK102456 and AG055379 to J.D.L.; no. DK114220 to L.R.), the Michigan Diabetes Research Center (grant no. DK020572), and the Michigan Nutrition and Obesity Center (grant no. DK089503).

Author information

Affiliations

Authors

Contributions

J.D.L. and Q.W. conceived the project and designed the research. Q.W., V.P.S., H.S., Y.X., Q.Z., X.X., L.G., H. S., S.L., L.R., and L.J. performed the experiments and analysed the data. K.O. provided the Tsk knockout mouse strain. J.D.L. and Q.W. wrote the manuscript.

Corresponding author

Correspondence to Jiandie D. Lin.

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 Figures 1–8 and Supplementary Table 3

Reporting Summary

Supplementary Table 1

Microarray expression values for mouse secretome genes

Supplementary Table 2

List of liver-enriched secretome genes

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, Q., Sharma, V.P., Shen, H. et al. The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation. Nat Metab 1, 251–260 (2019). https://doi.org/10.1038/s42255-018-0020-9

Download citation

Further reading