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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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).
The authors declare no competing interests.
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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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