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-gamma coactivator-1 alpha (PGC-1 alpha) 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-1 alpha after overfeeding. Interestingly, this reduction of the sirtuin PGC-1 alpha 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-1 alpha 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.
Sonia Karaz, Umberto De Marchi, Vincenzo Sorrentino, Federico Sizzano
Maria del Carmen Sandi Perez, Dogukan Hazar Ülgen, Silvie Rosalie Ruigrok