The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation
Open accessAbstract
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 show 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 are elevated in obesity. TSK deficiency increases sympathetic innervation and norepinephrine release in adipose tissue, leading to enhanced adrenergic signaling and thermogenesis, attenuation of brown fat whitening and protection from diet-induced obesity in mice. Our work reveals 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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Hepatic and plasma levels of TSK are strongly induced by stimuli that increase thermogenesis and energy expenditure, including adrenergic agonists and cold exposure.
“Hepatic and plasma levels of TSK were strongly induced by different stimuli that increased thermogenesis and energy expenditure, including adrenergic agonists and cold exposure [271].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [271]
TSK-deficient mice are resistant to diet-induced obesity, insulin resistance, and hepatic steatosis as a result of enhanced sympathetic activation and brown fat thermogenesis.
“TSK-deficient mice were resistant to diet-induced obesity, insulin resistance, and hepatic steatosis as a result of enhanced sympathetic activation and brown fat thermogenesis [271].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [271]
TSK was recently identified as an atypical member of the small leucine-rich proteoglycan family that regulates developmental processes in various organisms.
“TSK was recently identified as an atypical member of the small leucine-rich proteoglycan family that regulates developmental processes in various organisms [[269], [270], [271]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [271]
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- Authors
- Wang, Q., Sharma, V. P., Shen, H., Xiao, Y., Zhu, Q., Xiong, X., Guo, L., Jiang, L., Ohta, K., Li, S., Shi, H., Rui, L., & Lin, J. D.
- Affiliations
- University of Michigan (US)
- Miami University (US)
- Kumamoto University (JP)
- Corresponding author
- Lin, Jiandie D.
- ORCID
- Venue
- Nature Metabolism
- Published
- 2019-01-14
- Volume
- 1
- Issue
- 2
- Pages
- 251-260
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC6750233
- OpenAlex
- W2905593148
- Cited by
- 71
- References
- 54
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 10 · 2022: 15 · 2021: 12 · 2020: 8 · 2019: 10 · 2018: 1
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R21AG055379)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118731, P30DK034933, P60DK020572, R01DK112800, R01DK114220, R01DK102456, P30DK020572, P30DK089503)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- Tsukushi, hepatokines, energy expenditure, thermogenesis, brown adipose tissue, sympathetic innervation, noradrenaline release, obesity, diet-induced obesity, negative feedback regulation, adrenergic signaling
- MeSH terms
- Animals, Adipose Tissue, Brown, Energy Metabolism, Liver, Obesity, Proteoglycans, Thermogenesis, Mice
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