Seyssel K, Alligier M, Meugnier E, Chanseaume E, Loizon E, Canto C, Disse E, Lambert-Porcheron S, Brozek J, Blond E, Rieusset J, Morio B, Laville M, Vidal H
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.
J Clin Endocrinol Metab. 2014 Jul;99(7):E1254-62. doi: 10.1210/jc.2013-4379. Epub 2014 Mar 31.
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.
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.
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.
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.
背景/目的：本研究旨在评估健康男性在脂质过量喂养期间骨骼肌中燃料分配和能量代谢的调节情况。设计/参与者/干预措施：39名健康志愿者采用高脂饮食（3180千焦/天）过量喂养56天。在饮食前、饮食结束时的空腹状态以及测试餐期间通过间接测热法对能量代谢进行表征。在第0天和第56天采集骨骼肌活检样本。
测量骨骼肌中基因表达、线粒体呼吸、烟酰胺腺嘌呤二核苷酸（NAD(+)）含量以及过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）的乙酰化变化。
过量喂养使体重增加（+2.6千克）和脂肪量增加，同时能量燃料的底物使用发生转变，从优先氧化脂质转向优先氧化碳水化合物。脂质代谢基因表达的变化支持了这一观察结果，丙酮酸脱氢酶激酶4表达降低，这可能是NAD(+)浓度降低和沉默调节蛋白去乙酰化酶活性降低的结果，过量喂养后PGC-1α的高度乙酰化支持了这一点。有趣的是，在这些条件下沉默调节蛋白PGC-1α途径的这种降低与线粒体基因表达增加和呼吸速率升高有关。
人体肌肉对脂质过量喂养的适应和燃料分配的调节似乎依赖于沉默调节蛋白-PGC-1α途径在脂肪酸氧化和线粒体调节方面的调节功能之间的解离。这可能有助于在能量正平衡期间储存脂质，同时维持线粒体功能和氧化能力。
