Gene expression profiling of human skeletal muscle in response to stabilized weight loss

Background: Diet-induced weight reduction promotes a decrease in resting energy expenditure that could partly explain the difficulty in maintaining reduced body mass. Whether this reduction remains after stabilized weight loss is still controversial, and the molecular mechanisms are unknown. Objective: The objective was to investigate the effect of a stabilized 10% weight loss on body composition, metabolic profile, and skeletal muscle gene expression profiling. Design: Obese women were assigned to a 4-wk very-low-calorie diet, a 3-6-wk low-calorie diet, and a 4-wk weight-maintenance program to achieve a 10% weight loss. Resting energy expenditure, body composition, plasma variables, and skeletal muscle transcriptome were compared before weight loss and during stabilized weight reduction. Results: Energy restriction caused an 11% weight loss. Stabilization to the new weight was accompanied by an 11% decrease in the resting metabolic rate normalized to the body cellular mass. A large number of genes were regulated with a narrow range of regulation. The main regulated genes were slow/oxidative fiber markers, which were overexpressed, and the gene encoding the glucose metabolism inhibitor PDK4, which tended to be down-regulated. The knowledge-based approach gene set enrichment analysis showed that a set of genes related to long-term calorie restriction was up-regulated, whereas sets of genes related to insulin, interleukin 6, and ubiquitin-mediated proteolysis were down regulated. Conclusions: Weight loss-induced decreases in resting metabolic rate persist after weight stabilization. Changes in skeletal muscle gene expression indicate a shift toward oxidative metabolism.