A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21

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.

Automated summary

This study demonstrates that JNK signaling in adipocytes results in an increased circulating concentration of FGF21, regulating systemic metabolism. This mechanism of organ crosstalk involves a feed-forward regulatory loop mediated by JNK-regulated FGF21 autocrine signaling in adipocytes, promoting the expression of adiponectin and hepatic expression of FGF21. The novel signaling paradigm connects autocrine and endocrine signaling modes of the same hormone in different tissues.