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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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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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


  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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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.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Jiandie D. Lin.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–8 and Supplementary Table 3

  2. Reporting Summary

  3. Supplementary Table 1

    Microarray expression values for mouse secretome genes

  4. Supplementary Table 2

    List of liver-enriched secretome genes

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