Differential regulation of metabolic genes in skeletal muscle during starvation and refeeding in humans.
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 dehydrogenase 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.
Tsintzas
Kostas
K
Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK. kostas.tsintzas@nottingham.ac.uk
Jewell
Kirsty
K
Kamran
Mo
M
Laithwaite
David
D
Boonsong
Tantip
T
Littlewood
Julie
J
Macdonald
Ian
I
Bennett
Andrew
A
D000222:Adaptation, Physiological; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004435:Eating / Q000502:physiology*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013217:Starvation / Q000201:enzymology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D004040:Dietary Carbohydrates; D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D006593:Hexokinase; D005947:Glucose