Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism
Open accessAbstract
Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition.
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Steatosis is more closely related to the development of insulin resistance than obesity itself.
“In humans, plasma levels of fetuin-B are elevated in obese people with fatty liver and DM2, and studies have shown that steatosis is more closely related to the development of insulin resistance than obesity itself.”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [66]
Fetuin-B decreases insulin sensitivity in muscle and hepatocytes in culture when administered at physiological concentrations.
“Indeed, it has been shown that fetuin-B decreases insulin sensitivity in muscle and hepatocytes in culture when administered to them in physiological concentrations, and, in this situation, it was not able to activate pro-inflammatory signaling [66].”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [66]
In humans, plasma levels of fetuin-B are elevated in obese people with fatty liver and type 2 diabetes mellitus (DM2).
“In humans, plasma levels of fetuin-B are elevated in obese people with fatty liver and DM2, and studies have shown that steatosis is more closely related to the development of insulin resistance than obesity itself.”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [66]
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References 59 · Cited by 255
- Authors
- Meex, R. C., Hoy, A. J., Morris, A., Brown, R. D., Lo, J. C. Y., Burke, M., Goode, R. J. A., Kingwell, B. A., Kraakman, M. J., Febbraio, M. A., Greve, J. W., Rensen, S. S., Molloy, M. P., Lancaster, G. I., Bruce, C. R., & Watt, M. J.
- Affiliations
- Monash University (AU)
- National Institute for Medical Research (GB)
- Baker Heart and Diabetes Institute (AU)
- Garvan Institute of Medical Research (AU)
- Maastricht University Medical Centre (NL)
- Macquarie University (AU)
- Corresponding author
- Watt, Matthew J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 22
- Issue
- 6
- Pages
- 1078-1089
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2178232050
- Cited by
- 255
- References
- 59
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 22 · 2023: 27 · 2022: 23 · 2021: 37 · 2020: 24 · 2019: 33 · 2018: 25 · 2017: 19 · 2016: 8 · 2015: 1
- FWCI
- 13.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Deakin Research Online (Deakin University) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Diabetes Australia Research Trust
- Diabetes Australia
- Monash University
- National Health and Medical Research Council (1061278, 606460, 1077703, 1059454, 606766)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- fetuin-B, hepatic steatosis, hepatokines, insulin resistance, type 2 diabetes, impaired glucose tolerance, inflammation, myotubes, obesity, overnutrition, glucose metabolism
- MeSH terms
- Adult, Alanine Transaminase, Animals, Aspartate Aminotransferases, Cells, Cultured, Diabetes Mellitus, Type 2, Fatty Liver, Female, Glucose, Humans, Insulin Resistance, Liver, Male, Mice, Inbred C57BL, Mice, Obese, Middle Aged, Up-Regulation, Hepatocytes, RNA Interference, JNK Mitogen-Activated Protein Kinases, Mice, I-kappa B Kinase, Diet, High-Fat, Fetuin-B
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