Changes in gene expression in skeletal muscle in response to fat overfeeding in lean men. Obesity. 2007;15: 2583-2594. 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 ϳ550 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 Ϯ 0.3 kg) and waist circumference (2.2 Ϯ 0.5 cm, p ϭ 0.005) and a significant decrease in fasting non-esterified fatty acid plasma levels (Ϫ29 Ϯ 5%, p ϭ 0.028). Respiratory quotient was significantly increased (0.84 Ϯ 0.01 to 0.88 Ϯ 0.02, p ϭ 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.

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