Affordable Access

deepdyve-link
Publisher Website

The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation.

Authors
  • El-Merahbi, Rabih1
  • Viera, Jonathan Trujillo1
  • Valdes, Angel Loza1, 2
  • Kolczynska, Katarzyna1, 2
  • Reuter, Saskia1
  • Löffler, Mona C1
  • Erk, Manuela1
  • Ade, Carsten P3
  • Karwen, Till1
  • Mayer, Alexander E1
  • Eilers, Martin3
  • Sumara, Grzegorz1, 2
  • 1 Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany. , (Germany)
  • 2 Nencki Institute of Experimental Biology, PAS, 02-093 Warsaw, Poland. , (Poland)
  • 3 Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. , (Germany)
Type
Published Article
Journal
Genes & development
Publication Date
Apr 01, 2020
Volume
34
Issue
7-8
Pages
495–510
Identifiers
DOI: 10.1101/gad.333617.119
PMID: 32139423
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that β-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes. © 2020 El-Merahbi et al.; Published by Cold Spring Harbor Laboratory Press.

Report this publication

Statistics

Seen <100 times