Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06520, USA.
Genes Dev. 2021 Jan 1;35(1-2):133-146. doi: 10.1101/gad.344556.120. Epub 2020 Dec 17.
The cJun NH-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.
cJun 氨基末端激酶（JNK）信号通路可被代谢应激激活，促进代谢综合征的发展，包括高血糖、高血脂和胰岛素抵抗。这种综合的生理反应涉及不同器官之间的串扰。在这里，我们证明脂肪细胞中的 JNK 信号会导致循环中肝源性激素成纤维细胞生长因子 21（FGF21）的浓度升高，从而调节全身代谢。器官串扰的机制是由 JNK 调节的 FGF21 自分泌信号在脂肪细胞中引起的正反馈调节环介导的，该调节环促进脂肪因子脂联素的表达增加，随后肝脏表达激素 FGF21。器官串扰的机制将循环脂联素置于由脂肪细胞表达的自分泌 FGF21 的下游，而位于由肝细胞表达的内分泌 FGF21 的上游。这种调节环代表了一种新的信号传递范例，将同一激素在不同组织中的自分泌和内分泌信号传递模式联系起来。
