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

  1. Roger J. Davis1
  1. 1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
  2. 2Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06520, USA;
  3. 3Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut 06520, USA;
  4. 4Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  5. 5Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  6. 6Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  7. 7Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
  1. Corresponding author: roger.davis{at}umassmed.edu
  • 8 Present address: Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Sao Paulo 05508-000, Brazil.

Abstract

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.

Keywords

Footnotes

  • Supplemental material is available for this article.

  • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.344556.120.

  • Freely available online through the Genes & Development Open Access option.

  • Received September 5, 2020.
  • Accepted November 2, 2020.

This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

| Table of Contents
OPEN ACCESS ARTICLE

Life Science Alliance