K Seyssel1, M Alligier, E Meugnier, E Chanseaume, E Loizon, C Canto, E Disse, S Lambert-Porcheron, J Brozek, E Blond, J Rieusset, B Morio, M Laville, H Vidal. 1. INSERM Unité Mixte de Recherche 1060 (K.S., M.A., E.M., E.L., E.D., E.B., J.R., M.L., H.V.), Laboratoires CarMeN et Centre Européen pour la Nutrition et la Santé, Université Lyon 1, F-69600 Oullins, France; Centre de Recherche en Nutrition Humaine Rhône-Alpes (K.S., M.A., E.D., S.L.-P., E.B., M.L., H.V.), Centre Hospitalier Lyon-Sud, F-69310 Pierre Bénite, France; Institut National de la Recherche Agronomique Unité 1235 (E.M., J.R., M.L., H.V.), F-69600 Oullins, France; Institut National de la Recherche Agronomique Unité Mixte de Recherche 1019 (E.C., B.M.), Unité de Nutrition Humaine and Centre de Recherche en Nutrition Humaine Auvergne, Université d'Auvergne, F-63000 Clermont-Ferrand, France; Laboratory of Integrative and Systems Physiology (C.C.), Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences - Institute of Bioengineering, CH-1015 Lausanne, Switzerland; and Genfit (J.B.), F-59120 Loos, France.
Abstract
CONTEXT/ OBJECTIVE: The aim of this study was to evaluate the regulation of the fuel partitioning and energy metabolism in skeletal muscle during lipid overfeeding in healthy men. Design/Participants/Intervention: Thirty-nine healthy volunteers were overfed for 56 days with a high-fat diet (3180 kJ/d). Energy metabolism (indirect calorimetry) was characterized in the fasting state and during a test meal before and at the end of the diet. Skeletal muscle biopsies were taken at day 0 and day 56. MAIN OUTCOME MEASURES: Change in gene expression, mitochondrial respiration, nicotinamide adenine dinucleotide (NAD(+)) content, and acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle was measured. RESULTS: Overfeeding increased body weight (+2.6 kg) and fat mass concomitantly with a shift in the use of substrates as energy fuel toward preferential oxidation of carbohydrates instead of lipids. Changes in lipid metabolic gene expression supported this observation, with a reduction in pyruvate dehydrogenase kinase 4 expression that could be the consequences of decreased NAD(+) concentration and reduced deacetylase activity of the sirtuins, as supported by hyperacetylation of PGC-1α after overfeeding. Interestingly, this reduction of the sirtuin PGC-1α pathway was associated with increased mitochondrial gene expression and higher respiration rate under these conditions. CONCLUSION: Adaptation to lipid overfeeding and regulation of fuel partitioning in human muscle appear to rely on a dissociation between the regulatory functions of the sirtuin-PGC-1α pathway on fatty acid oxidation and on mitochondrial regulation. This may facilitate lipid storage during a period of positive energy balance while maintaining mitochondrial functions and oxidative capacities.
CONTEXT/ OBJECTIVE: The aim of this study was to evaluate the regulation of the fuel partitioning and energy metabolism in skeletal muscle during lipid overfeeding in healthy men. Design/Participants/Intervention: Thirty-nine healthy volunteers were overfed for 56 days with a high-fat diet (3180 kJ/d). Energy metabolism (indirect calorimetry) was characterized in the fasting state and during a test meal before and at the end of the diet. Skeletal muscle biopsies were taken at day 0 and day 56. MAIN OUTCOME MEASURES: Change in gene expression, mitochondrial respiration, nicotinamide adenine dinucleotide (NAD(+)) content, and acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle was measured. RESULTS: Overfeeding increased body weight (+2.6 kg) and fat mass concomitantly with a shift in the use of substrates as energy fuel toward preferential oxidation of carbohydrates instead of lipids. Changes in lipid metabolic gene expression supported this observation, with a reduction in pyruvate dehydrogenase kinase 4 expression that could be the consequences of decreased NAD(+) concentration and reduced deacetylase activity of the sirtuins, as supported by hyperacetylation of PGC-1α after overfeeding. Interestingly, this reduction of the sirtuin PGC-1α pathway was associated with increased mitochondrial gene expression and higher respiration rate under these conditions. CONCLUSION: Adaptation to lipid overfeeding and regulation of fuel partitioning in human muscle appear to rely on a dissociation between the regulatory functions of the sirtuin-PGC-1α pathway on fatty acid oxidation and on mitochondrial regulation. This may facilitate lipid storage during a period of positive energy balance while maintaining mitochondrial functions and oxidative capacities.
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