Title :

FTO contributes to hepatic metabolism regulation through regulation of leptin action and STAT3 signalling in liver.

Author(s) :

Bravard, Amélie [Auteur]
Cardiovasculaire, métabolisme, diabétologie et nutrition [CarMeN]
Vial, Guillaume [Auteur]
Cardiovasculaire, métabolisme, diabétologie et nutrition [CarMeN]
Chauvin, Marie-Agnès [Auteur]
Cardiovasculaire, métabolisme, diabétologie et nutrition [CarMeN]
Rouillé, Yves [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Bailleul, Bernard [Auteur]
Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]
Vidal, Hubert [Auteur]
Cardiovasculaire, métabolisme, diabétologie et nutrition [CarMeN]
Rieusset, Jennifer [Auteur correspondant]
Cardiovasculaire, métabolisme, diabétologie et nutrition [CarMeN]

Journal title :

Cell Communication and Signaling

Pages :

4

Publisher :

BioMed Central

Publication date :

2014

ISSN :

1478-811X

English keyword(s) :

Leptin receptor-STAT3 pathway
Mitochond ria
Glucose homeostasis
Liver
FTO

HAL domain(s) :

Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire/Biochimie [q-bio.BM]
Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire

English abstract : [en]

BACKGROUND: The fat mass and obesity associated (FTO) gene is related to obesity and type 2 diabetes, but its function is still largely unknown. A link between leptin receptor-signal transducers and activators of transcription ...
Show more >BACKGROUND: The fat mass and obesity associated (FTO) gene is related to obesity and type 2 diabetes, but its function is still largely unknown. A link between leptin receptor-signal transducers and activators of transcription 3 (LepR-STAT3) signalling pathway and FTO was recently suggested in the hypothalamus. Because of the presence of FTO in liver and the role of LepR-STAT3 in the control of hepatic metabolism, we investigated both in vitro and in vivo the potential interrelationship between FTO and LepR-STAT3 signalling pathway in liver and the impact of FTO overexpression on leptin action and glucose homeostasis in liver of mice. RESULTS: We found that FTO protein expression is regulated by both leptin and IL-6, concomitantly to an induction of STAT3 tyrosine phosphorylation, in leptin receptor (LepRb) expressing HuH7 cells. In addition, FTO overexpression in vitro altered both leptin-induced Y705 and S727 STAT3 phosphorylation, leading to dysregulation of glucose-6-phosphatase (G6P) expression and mitochondrial density, respectively. In vivo, liver specific FTO overexpression in mice induced a reducetion of Y705 phosphorylation of STAT3 in nuclear fraction, associated with reduced SOCS3 and LepR mRNA levels and with an increased G6P expression. Interestingly, FTO overexpression also induced S727 STAT3 phosphorylation in liver mitochondria, resulting in an increase of mitochondria function and density. Altogether, these data indicate that FTO promotes mitochondrial recruitment of STAT3 to the detriment of its nuclear localization, affecting in turn oxidative metabolism and the expression of leptin-targeted genes. Interestingly, these effects were associated in mice with alterations of leptin action and hyperleptinemia, as well as hyperglycemia, hyperinsulinemia and glucose intolerance. CONCLUSIONS: Altogether, these data point a novel regulatory loop between FTO and leptin-STAT3 signalling pathways in liver cells, and highlight a new role of FTO in the regulation of hepatic leptin action and glucose metabolism.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Collections :

• Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (RNMCD) - U1011

Source :

Harvested from HAL