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. This chronic oxidative stress also favors accumulation of lipid droplets. 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. In this work, we show that mice lacking TP53INP1 are prone to redox-driven obesity and insulin resistance. A genome-wide association study (GWAS) published in 2010 identified TP53INP1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. T2D is characterized by insulin resistance resulting from both environmental and genetic factors.
The metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). 11 Islet Cell Laboratory, University of Pisa – Cisanello Hospital, Pisa, Italy.10 Cell Biology, Department of Medicine, Imperial College, London, UK.9 Centre Hospitalier Universitaire de Nice, Pôle Digestif, Hôpital L'Archet, Nice, France.8 Université de Nice-Sophia-Antipolis, Nice, France.7 Inserm, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France.6 CNRS, UMR5203, Inserm, U661, Universités de Montpellier 1 & 2, IGF, Montpellier, France.5 Inserm, U1069, Nutrition, Croissance et Cancer (N2C), Tours, France.4 CNRS, UMR7258, CRCM, Marseille, France.3 Aix-Marseille Université, Marseille, France.2 Institut Paoli-Calmettes, Marseille, France.1 Inserm, U1068, CRCM, Marseille, France.
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