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

Cell Communication and Signaling

Research

Marie-Agnès Chauvin¹  Hubert Vidal¹  Amélie Bravard¹  Guillaume Vial¹  Jennifer Rieusset²  Bernard Bailleul³  Yves Rouillé⁴ 

[1] INSERM U-1060, Laboratoire CarMeN, Université Lyon 1, INRA 1235, INSA de Lyon, Facultés de médecine Charles Mérieux, Lyon-Sud, Oullins, France;INSERM U-1060, Laboratoire CarMeN, Université Lyon 1, INRA 1235, INSA de Lyon, Facultés de médecine Charles Mérieux, Lyon-Sud, Oullins, France;UMR INSERM U1060, Faculté de médecine Lyon-Sud, 165 chemin du grand Revoyet, BP12 69921, Oullins cedex, France;INSERM UMR-1011, Université Lille 2, Institut Pasteur de Lille, Lille, France;Inserm U1019, CNRS UMR8204, Center for Infection & Immunity of Lille (CIIL), Institut Pasteur de Lille, Université Lille Nord de France, Lille, France;

关键词: FTO;    Liver;    Glucose homeostasis;    Mitochondria;    Leptin receptor-STAT3 pathways;   

DOI  :  10.1186/1478-811X-12-4

 received in 2013-09-18, accepted in 2014-01-04,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsWe 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.ConclusionsAltogether, 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.

【 授权许可】

Unknown   
© Bravard et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.