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.
Subject(s)
Dietary Fats/administration & dosage , Energy Metabolism , Mitochondria, Muscle/physiology , Muscle, Skeletal/metabolism , Overnutrition/metabolism , Adult , Cell Respiration/drug effects , Cell Respiration/genetics , Diet, High-Fat , Energy Metabolism/drug effects , Energy Metabolism/genetics , Humans , Lipid Metabolism/drug effects , Lipid Metabolism/genetics , Male , Mitochondria, Muscle/drug effects , Muscle, Skeletal/drug effects , Overnutrition/genetics , Oxidation-ReductionABSTRACT
CONTEXT: Deciphering the early processes occurring in adipose tissue during weight gain is a major issue for understanding the development of fat mass and obesity. Experimental overfeeding in humans is a unique situation to tackle these events. OBJECTIVE: Our aim was to identify the pathways involved in sc adipose tissue remodeling during the initial phase of weight gain. RESEARCH DESIGN AND METHODS: Forty-four healthy men were involved in an overfeeding protocol with a lipid-enriched diet (+760 kcal/d) for 2 months. Subcutaneous abdominal adipose tissue biopsies were taken for histology, transcriptomics, and Western blotting in the basal state, after 14 d, and at the end of the protocol. RESULTS: Overfeeding significantly increased body weight (+2.5 kg) and fat mass. Reorganization of gene expression patterns occurred in adipose tissue with an up-regulation of numerous genes involved in lipid metabolism and storage, followed by clusters of genes related to angiogenesis and extracellular matrix remodeling. Histological examination showed increased microvascular density and connective tissue deposition after 56 d of overfeeding, with no changes in the number of macrophages or inflammatory cells. Inhibition of the canonical Wnt/ß-catenin signaling pathway and induction of the renin-angiotensin system might be implicated in the remodeling of sc adipose tissue. CONCLUSIONS: We characterize the coordinated and time-dependent processes that occur in human adipose tissue during the early phase of weight gain in healthy subjects and identify pathways representing potential targets in pathologies of adipose development, including obesity.
Subject(s)
Overnutrition/physiopathology , Subcutaneous Fat, Abdominal/physiology , Weight Gain/physiology , Adiposity/genetics , Adiposity/physiology , Adolescent , Adult , Eating/genetics , Eating/physiology , Gene Expression Profiling , Humans , Male , Microarray Analysis , Middle Aged , Overnutrition/complications , Overnutrition/genetics , Overnutrition/metabolism , Signal Transduction/genetics , Subcutaneous Fat, Abdominal/metabolism , Time Factors , Weight Gain/genetics , Young AdultABSTRACT
In contrast with senescence-accelerated mice R1, SAM P8 show abnormal aging characteristics. Changes occurring during aging could be mainly caused by free radical reactions. The brain is a plasmalogen-rich tissue. These particular phospholipids may act as endogenous antioxidants, be oxidized and release long chain aldehydes and alpha-hydroxyaldehydes during oxidative stress. The aim of this study was to examine by GC/MS the age- and strain-related levels of plasmalogens, aldehydes and alpha-hydroxyaldehydes in brain homogenates of SAM P8 and R1 at weaning, 5 months and 9 months of age in order to better understand the differences between both strains. In SAM R1, the evolution of brain plasmalogen levels corresponded to characteristics of normal aging: an increase from weaned to adult mice followed by a decrease characterizing the normal loss of myelin. By contrast to SAM R1, there was no change in the plasmalogen content in SAM P8 brain. The levels of aldehydes and alpha-hydroxyaldehydes were similar for both strains, they remained constant between adult and aged mice. Specific changes in the aging of SAM P8 were not explained by cerebral levels of these oxidative products. Other mechanisms related to the toxicity of aldehydes and alpha-hydroxyaldehydes could be considered.
