A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21
Open accessAbstract
The cJun NH 2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism. The mechanism of organ crosstalk is mediated by a feed-forward regulatory loop caused by JNK-regulated FGF21 autocrine signaling in adipocytes that promotes increased expression of the adipokine adiponectin and subsequent hepatic expression of the hormone FGF21. The mechanism of organ cross-talk places circulating adiponectin downstream of autocrine FGF21 expressed by adipocytes and upstream of endocrine FGF21 expressed by hepatocytes. This regulatory loop represents a novel signaling paradigm that connects autocrine and endocrine signaling modes of the same hormone in different tissues.
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Adiponectin is not required for FGF21 signalling; adiponectin may induce physiological FGF21 production from the liver.
“more recent studies have confirmed that adiponectin is not required for FGF21 signalling but instead have suggested that adiponectin may induce physiological FGF21 production from the liver10.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [10]
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References 60 · Cited by 43
- Authors
- Han, M. S., Perry, R. J., Camporez, J.-P., Scherer, P. E., Shulman, G. I., Gao, G., & Davis, R. J.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Yale University (US)
- The University of Texas Southwestern Medical Center (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2020-12-17
- Volume
- 35
- Issue
- 1-2
- Pages
- 133-146
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC7778269
- OpenAlex
- W3114921148
- Cited by
- 43
- References
- 60
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 6 · 2023: 8 · 2022: 15 · 2021: 6
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by-nc)
- Funders
- American Heart Association (19CDA34660270)
- Sao Paulo Research Foundation (2018/04956-5)
- National Institutes of Health (R01 DK107220, R01 DK112698, R00 CA215315, R01 DK55758, P01 AG051459, R01 DK116774, R01 DK114793, P30 DK045735)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- FGF21, JNK signaling, adipocytes, adiponectin, organ crosstalk, autocrine signaling, hormone signaling, hepatokines, metabolic syndrome, insulin resistance, adipose tissue
- MeSH terms
- Adipose Tissue, Animals, Endocrine System, Energy Metabolism, Fibroblast Growth Factors, Gene Expression Regulation, Insulin Resistance, Liver, Signal Transduction, Adipocytes, Autocrine Communication, MAP Kinase Signaling System, Hepatocytes, Feedback, Physiological, MAP Kinase Kinase 4, Mice, Adiponectin
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