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

Autor: Yves Rouillé, Jennifer Rieusset, Guillaume Vial, Team1 Carmen, Hubert VIDAL, Team2 Carmen, Carmen Lab, Marie-Agnes BERGER
Přispěvatelé: Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Inserm, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), BMC, Ed., Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Rok vydání: 2013
Předmět:
Mitochond ria
endocrine system diseases
Mitochondria
Liver
Suppressor of Cytokine Signaling Proteins
Glucose homeostasis
Biochemistry
Mixed Function Oxygenases
chemistry.chemical_compound
Mice
FTO
Liver
Mitochondria
Leptin receptor-STAT3 pathways
SOCS3
10. No inequality
[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
Cells
Cultured
Leptin
digestive
oral
and skin physiology
Oxo-Acid-Lyases
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biomolecules [q-bio.BM]
Protein Transport
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
Phosphorylation
Receptors
Leptin
Signal transduction
Signal Transduction
STAT3 Transcription Factor
medicine.medical_specialty
Glucose-6-Phosphate
Biology
Internal medicine
Cell Line
Tumor
medicine
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
RNA
Messenger
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
Molecular Biology
Leptin receptor
Leptin receptor-STAT3 pathway
Research
nutritional and metabolic diseases
Tyrosine phosphorylation
Cell Biology
Rats
Mice
Inbred C57BL
Endocrinology
chemistry
Suppressor of Cytokine Signaling 3 Protein
Mutation
Zdroj: Cell Communication and Signaling : CCS
Cell Communication and Signaling
Cell Communication and Signaling, BioMed Central, 2014, 12 (1), pp.4. ⟨10.1186/1478-811X-12-4⟩
Cell Communication and Signaling, 2014, 12 (1), pp.4. ⟨10.1186/1478-811X-12-4⟩
Cell Communication and Signaling (12), . (2014)
ISSN: 1478-811X
DOI: 10.1186/1478-811X-12-4⟩
Popis: Background: [br/] 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.[br/] Results: [br/] 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. [br/] Conclusions: [br/] 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.
Databáze: OpenAIRE
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