TY - JOUR
T1 - Hepatic posttranscriptional network comprised of CCR4–NOT deadenylase and FGF21 maintains systemic metabolic homeostasis
AU - Morita, Masahiro
AU - Siddiqui, Nadeem
AU - Katsumura, Sakie
AU - Rouya, Christopher
AU - Larsson, Ola
AU - Nagashima, Takeshi
AU - Hekmatnejad, Bahareh
AU - Takahashi, Akinori
AU - Kiyonari, Hiroshi
AU - Zang, Mengwei
AU - St-Arnaud, René
AU - Oike, Yuichi
AU - Giguère, Vincent
AU - Topisirovic, Ivan
AU - Okada-Hatakeyama, Mariko
AU - Yamamoto, Tadashi
AU - Sonenberg, Nahum
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/4/16
Y1 - 2019/4/16
N2 - Whole-body metabolic homeostasis is tightly controlled by hormone-like factors with systemic or paracrine effects that are derived from nonendocrine organs, including adipose tissue (adipokines) and liver (hepatokines). Fibroblast growth factor 21 (FGF21) is a hormone-like protein, which is emerging as a major regulator of whole-body metabolism and has therapeutic potential for treating metabolic syndrome. However, the mechanisms that control FGF21 levels are not fully understood. Herein, we demonstrate that FGF21 production in the liver is regulated via a posttranscriptional network consisting of the CCR4–NOT deadenylase complex and RNA-binding protein tristetraprolin (TTP). In response to nutrient uptake, CCR4–NOT cooperates with TTP to degrade AU-rich mRNAs that encode pivotal metabolic regulators, including FGF21. Disruption of CCR4–NOT activity in the liver, by deletion of the catalytic subunit CNOT6L, increases serum FGF21 levels, which ameliorates diet-induced metabolic disorders and enhances energy expenditure without disrupting bone homeostasis. Taken together, our study describes a hepatic CCR4–NOT/FGF21 axis as a hitherto unrecognized systemic regulator of metabolism and suggests that hepatic CCR4–NOT may serve as a target for devising therapeutic strategies in metabolic syndrome and related morbidities.
AB - Whole-body metabolic homeostasis is tightly controlled by hormone-like factors with systemic or paracrine effects that are derived from nonendocrine organs, including adipose tissue (adipokines) and liver (hepatokines). Fibroblast growth factor 21 (FGF21) is a hormone-like protein, which is emerging as a major regulator of whole-body metabolism and has therapeutic potential for treating metabolic syndrome. However, the mechanisms that control FGF21 levels are not fully understood. Herein, we demonstrate that FGF21 production in the liver is regulated via a posttranscriptional network consisting of the CCR4–NOT deadenylase complex and RNA-binding protein tristetraprolin (TTP). In response to nutrient uptake, CCR4–NOT cooperates with TTP to degrade AU-rich mRNAs that encode pivotal metabolic regulators, including FGF21. Disruption of CCR4–NOT activity in the liver, by deletion of the catalytic subunit CNOT6L, increases serum FGF21 levels, which ameliorates diet-induced metabolic disorders and enhances energy expenditure without disrupting bone homeostasis. Taken together, our study describes a hepatic CCR4–NOT/FGF21 axis as a hitherto unrecognized systemic regulator of metabolism and suggests that hepatic CCR4–NOT may serve as a target for devising therapeutic strategies in metabolic syndrome and related morbidities.
KW - CCR4–NOT
KW - Deadenylase
KW - FGF21
KW - Hepatokine
KW - Metabolic syndrome
UR - http://www.scopus.com/inward/record.url?scp=85064396751&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064396751&partnerID=8YFLogxK
U2 - 10.1073/pnas.1816023116
DO - 10.1073/pnas.1816023116
M3 - Article
C2 - 30926667
AN - SCOPUS:85064396751
SN - 0027-8424
VL - 116
SP - 7973
EP - 7981
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -