期刊
EMBO MOLECULAR MEDICINE
卷 7, 期 6, 页码 802-818出版社
WILEY
DOI: 10.15252/emmm.201404318
关键词
autophagy; diabetes; mitochondria; obesity; oxidative stress
资金
- Institut National de la Sante et de la Recherche Medicale
- Centre National de la Recherche Scientifique
- Institut National du Cancer
- Association pour la Recherche sur le Cancer
- La Ligue Nationale contre le Cancer
- University of Nice
- Programme Hospitalier de Recherche Clinique (Centre Hospitalier Universitaire of Nice)
- charity (Association Francaise pour l'Etude du Foie (AFEF/LFB))
- charity (European Foundation for the study of Diabetes EFSD/Lilly)
- French Government (National Research Agency, ANR) through the 'Investments for the Future' LABEX SIGNALIFE: program [ANR-11-LABX-0028-01]
- Wellcome Trust [WT098424AIA]
- MRC [MR/J0003042/1]
- Royal Society
- MRC [MR/K001981/1] Funding Source: UKRI
- Medical Research Council [MR/K001981/1] Funding Source: researchfish
The metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). T2D is characterized by insulin resistance resulting from both environmental and genetic factors. A genome-wide association study (GWAS) published in 2010 identified TP53INP1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP53INP1 are prone to redox-driven obesity and insulin resistance. Furthermore, we demonstrate that the reactive oxygen species increase in TP53INP1-deficient cells results from accumulation of defective mitochondria associated with impaired PINK/PARKIN mitophagy. This chronic oxidative stress also favors accumulation of lipid droplets. Taken together, our data provide evidence that the GWAS-identified TP53INP1 gene prevents metabolic syndrome, through a mechanism involving prevention of oxidative stress by mitochondrial homeostasis regulation. In conclusion, this study highlights TP53INP1 as a molecular regulator of redox-driven metabolic syndrome and provides a new preclinical mouse model for metabolic syndrome clinical research.
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