UMass Chan Medical School Faculty Publications

UMMS Affiliation

Program in Molecular Medicine; Horae Gene Therapy Center; Davis Lab

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Document Type



Biochemical Phenomena, Metabolism, and Nutrition | Cell Biology | Cellular and Molecular Physiology | Endocrine System | Endocrinology | Hormones, Hormone Substitutes, and Hormone Antagonists


The cJun NH2-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.


FGF21, JNK, autocrine, endocrine, organ cross-talk

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© 2021 Han et al.; Published by Cold Spring Harbor Laboratory Press. This article, published in Genes and Development, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at

DOI of Published Version



Han MS, Perry RJ, Camporez JP, Scherer PE, Shulman GI, Gao G, Davis RJ. A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21. Genes Dev. 2021 Jan 1;35(1-2):133-146. doi: 10.1101/gad.344556.120. Epub 2020 Dec 17. PMID: 33334822; PMCID: PMC7778269. Link to article on publisher's site

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Link to Article in PubMed

Journal/Book/Conference Title

Genes and development

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Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License