A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21
AuthorsHan, Myoung Souk
Perry, Rachel J.
Scherer, Philipp E.
Shulman, Gerald I.
Davis, Roger J.
Document TypeJournal Article
Biochemical Phenomena, Metabolism, and Nutrition
Cellular and Molecular Physiology
Hormones, Hormone Substitutes, and Hormone Antagonists
MetadataShow full item record
AbstractThe 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.
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