ABSTRACT
OBJECTIVE: The adaptive mechanisms in response to excess energy supply are still poorly known in humans. Our aims were to define metabolic responses and changes in gene expression in skeletal muscle of healthy volunteers during fat overfeeding. RESEARCH METHODS AND PROCEDURES: Eight lean young healthy men were given a diet rich in saturated fat with an excess of approximately 550 kcal/d for 4 weeks. Using oligonucleotide microarrays, gene expression changes in skeletal muscle were analyzed at Day 0, Day 14, and Day 28. RESULTS: Fat overfeeding led to an increase in body weight (1.0 +/- 0.3 kg) and waist circumference (2.2 +/- 0.5 cm, p = 0.005) and a significant decrease in fasting non-esterified fatty acid plasma levels (-29 +/- 5%, p = 0.028). Respiratory quotient was significantly increased (0.84 +/- 0.01 to 0.88 +/- 0.02, p = 0.034) and lipid oxidation rate tended to decrease. The expression of 55 genes was modified in skeletal muscle. The main pathways indicated a coordinated stimulation of triacylglycerol synthesis, inhibition of lipolysis, reduction of fatty acid oxidation, and development of adipocytes. Promoter analysis of the regulated genes suggests that sterol regulatory element binding proteins might be important players of the short-term adaptation to fat overfeeding in human skeletal muscle. DISCUSSION: This combined metabolic and genomic investigation shows that fat overfeeding for 28 days promotes the storage of the excess energy in lean men and demonstrates the usefulness of a transcriptomic approach to a better understanding of the metabolic adaptation to changes in nutritional behavior in human.
Subject(s)
Dietary Fats/pharmacology , Gene Expression Regulation/drug effects , Hyperphagia/metabolism , Muscle, Skeletal/metabolism , Thinness/metabolism , Adiponectin/blood , Adult , Biopsy , Body Composition/drug effects , Body Weight/drug effects , Fatty Acid Binding Protein 3 , Fatty Acid-Binding Proteins/genetics , Fatty Acid-Binding Proteins/metabolism , Humans , Lipolysis/drug effects , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , RNA, Messenger/metabolism , Sterol Regulatory Element Binding Proteins/genetics , Sterol Regulatory Element Binding Proteins/metabolism , Triglycerides/metabolismABSTRACT
To define the effects of acute hyperglycemia per se (i.e., without the confounding effect of hyperinsulinemia) in human tissues in vivo, we performed global gene expression analysis using microarrays in vastus lateralis muscle and subcutaneous abdominal adipose tissue of seven healthy men during a hyperglycemic-euinsulinemic clamp with infusion of somatostatin to inhibit endogenous insulin release. We found that doubling fasting blood glucose values while maintaining plasma insulin in the fasting range modifies the expression of 316 genes in skeletal muscle and 336 genes in adipose tissue. More than 80% of them were downregulated during the clamp, indicating a drastic effect of acute high glucose, in the absence of insulin, on mRNA levels in human fat and muscle tissues. Almost all the biological pathways were affected, suggesting a generalized effect of hyperglycemia. The induction of genes from the metallothionein family, related to detoxification and free radical scavenging, indicated that hyperglycemia-induced oxidative stress could be involved in the observed modifications. Because the duration and the concentration of the experimental hyperglycemia were close to what is observed during a postprandial glucose excursion in diabetic patients, these data suggest that modifications of gene expression could be an additional effect of glucose toxicity in vivo.