Mice Deficient in the Respiratory Chain Gene Cox6a2 Are Protected against High-Fat Diet-Induced Obesity and Insulin Resistance

Roel Quintens, Sarvjeet Singh, Katleen Lemaire, Katrien De Bock, Mikaela Granvik, Anica Schraenen, Irene Olga Cornelia Maria Vroegrijk, Veronica Costa, Pieter Van Noten, Dennis Lambrechts, Stefan Lehnert, Leentje Van Lommel, Lieven Thorrez, Geoffroy De Faudeur, Johannes Anthonius Romijn, John Michael Shelton, Luca Scorrano, Henri Roger Lijnen, Peter Jacobus Voshol, Peter Carmeliet, Pradeep Puthenveetil Abraham Mammen, Frans Schuit

Oxidative phosphorylation in mitochondria is responsible for 90% of ATP synthesis in most cells. This essential housekeeping function is mediated by nuclear and mitochondrial genes encoding subunits of complex I to V of the respiratory chain. Although complex IV is the best studied of these complexes, the exact function of the striated muscle-specific subunit COX6A2 is still poorly understood. In this study, we show that Cox6a2-deficient mice are protected against high-fat diet-induced obesity, insulin resistance and glucose intolerance. This phenotype results from elevated energy expenditure and a skeletal muscle fiber type switch towards more oxidative fibers. At the molecular level we observe increased formation of reactive oxygen species, constitutive activation of AMP-activated protein kinase, and enhanced expression of uncoupling proteins. Our data indicate that COX6A2 is a regulator of respiratory uncoupling in muscle and we demonstrate that a novel and direct link exists between muscle respiratory chain activity and diet-induced obesity/insulin resistance.