Endogenous GDF15 and FGF21 additively alleviate hepatic steatosis and insulin resistance in obese mice
Endogenous GDF15 and FGF21 additively alleviate hepatic steatosis and insulin resistance in obese mice
Summary Obesity in mice and humans is associated with elevated levels of at least two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear. Here we used tissue selective knockout mouse models to establish that, like FGF21, circulating GDF15 is primarily derived from the liver, rather than adipose tissue, muscle or macrophages in high fat fed mice. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in high fat fed mice but is associated with significantly greater hepatic steatosis and insulin resistance. Collectively the data suggest that activation of the integrated stress response in hepatocytes is a major driver for GDF15 and FGF21 secretion in the context of overfeeding, and that they both act to alleviate this metabolic stress.
Scurria Fabio、Bl¨1her Matthias、Small Kerrin S.、O?ˉRahilly Stephen、Guiu-Jurado Esther、Harrison James、Haider Afreen、Virtue Samuel、Bidault Guillaume、Savage David B.、Tadross John A.、Warner James、Alvarez-Guaita Anna、Zvetkova Ilona、El-sayed Moustafa Julia Sarah、Patel Satish
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic ScienceMedical Department III ¨C Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center||Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum M¨1nchen at the University of Leipzig and University Hospital LeipzigDepartment of Twin Research and Genetic Epidemiology, King?ˉs College LondonUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science||MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of CambridgeMedical Department III ¨C Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical CenterDepartment of Medicine, Division of Cardiovascular Medicine, University of CambridgeUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic ScienceUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic ScienceUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic ScienceUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic ScienceUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science||East Midlands and East of England Genomic Laboratory Hub & Department of Histopathology, Cambridge University Hospitals NHS Foundation TrustUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic ScienceUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic ScienceUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic ScienceDepartment of Twin Research and Genetic Epidemiology, King?ˉs College LondonUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science
基础医学生理学生物化学
GDF15FGF21insulin resistanceobesity
Scurria Fabio,Bl¨1her Matthias,Small Kerrin S.,O?ˉRahilly Stephen,Guiu-Jurado Esther,Harrison James,Haider Afreen,Virtue Samuel,Bidault Guillaume,Savage David B.,Tadross John A.,Warner James,Alvarez-Guaita Anna,Zvetkova Ilona,El-sayed Moustafa Julia Sarah,Patel Satish.Endogenous GDF15 and FGF21 additively alleviate hepatic steatosis and insulin resistance in obese mice[EB/OL].(2025-03-28)[2025-05-04].https://www.biorxiv.org/content/10.1101/2022.06.08.495255.点此复制
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