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The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation

Nature Metabolism volume 1, pages 251–260 (2019)Cite this article

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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.

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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.

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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.

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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).

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Authors and Affiliations

  1. Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, USA

    Qiuyu Wang, Vishal P. Sharma, Yuanyuan Xiao, Xuelian Xiong, Liang Guo, Siming Li & Jiandie D. Lin

  2. Department of Molecular & Integrated Physiology, University of Michigan Medical Center, Ann Arbor, MI, USA

    Hong Shen, Lin Jiang & Liangyou Rui

  3. Physiology and Neuroscience, Department of Biology, Miami University, Oxford, OH, USA

    Qi Zhu & Haifei Shi

  4. Department of Developmental Neurobiology, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan

    Kunimasa Ohta

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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.

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Correspondence to Jiandie D. Lin.

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Supplementary information

Supplementary Information

Supplementary Figures 1–8 and Supplementary Table 3

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Supplementary Table 1

Microarray expression values for mouse secretome genes

Supplementary Table 2

List of liver-enriched secretome genes

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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

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