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INTEGRATIVE |
1 Centre for Integrated Systems Biology and Medicine, Institute of Clinical Research
2 FRAME Alternatives Laboratory, School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, UK
This study investigated the molecular alterations underlying the physiological adaptations to starvation and refeeding in human skeletal muscle. Forty-eight hours' starvation reduced whole-body insulin sensitivity by 42% and produced marked changes in expression of key carbohydrate (CHO) regulatory genes and proteins: SREBP1c and hexokinase II (HKII) were downregulated 2.5- and 5-fold, respectively, whereas the pyruvate dexydrogenase kinase 4 (PDK4) was upregulated 4-fold. These responses were not dependent on the phosphorylation status of Akt and FOXO1. On the other hand, starvation and the concomitant increase in circulating free fatty acids did not upregulate the expression of transcription factors and genes involved in fat metabolism. Twenty-four hours' refeeding with a CHO-rich diet completely reversed the changes in PDK4, HKII and SREBP1c expression in human skeletal muscle but failed to fully restore whole-body insulin sensitivity. Thus, during starvation in healthy humans, unlike rodents, regulation of fat metabolism does not require an adaptive response at transcriptional level, but adaptive changes in gene expression are required to switch off oxidative glucose disposal. Lack of effect on key proteins in the insulin-signalling pathway may indicate that changes in intracellular substrate availability/flux may be responsible for these adaptive changes in glucose metabolism. This may represent an important aspect of the molecular basis of the development of insulin resistance in metabolic conditions characterized by energy restriction.
(Received 16 March 2006;
accepted after revision 6 June 2006;
first published online 8 June 2006)
Corresponding author K. Tsintzas: Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK. Email: kostas.tsintzas{at}nottingham.ac.uk
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