Fasting induces a biphasic adaptive metabolic response in murine small intestine.
BACKGROUND
The gut is a major energy consumer, but a comprehensive overview of the adaptive response to fasting is lacking. Gene-expression profiling, pathway analysis, and immunohistochemistry were therefore carried out on mouse small intestine after 0, 12, 24, and 72 hours of fasting.


RESULTS
Intestinal weight declined to 50% of control, but this loss of tissue mass was distributed proportionally among the gut's structural components, so that the microarrays' tissue base remained unaffected. Unsupervised hierarchical clustering of the microarrays revealed that the successive time points separated into distinct branches. Pathway analysis depicted a pronounced, but transient early response that peaked at 12 hours, and a late response that became progressively more pronounced with continued fasting. Early changes in gene expression were compatible with a cellular deficiency in glutamine, and metabolic adaptations directed at glutamine conservation, inhibition of pyruvate oxidation, stimulation of glutamate catabolism via aspartate and phosphoenolpyruvate to lactate, and enhanced fatty-acid oxidation and ketone-body synthesis. In addition, the expression of key genes involved in cell cycling and apoptosis was suppressed. At 24 hours of fasting, many of the early adaptive changes abated. Major changes upon continued fasting implied the production of glucose rather than lactate from carbohydrate backbones, a downregulation of fatty-acid oxidation and a very strong downregulation of the electron-transport chain. Cell cycling and apoptosis remained suppressed.


CONCLUSIONS
The changes in gene expression indicate that the small intestine rapidly looses mass during fasting to generate lactate or glucose and ketone bodies. Meanwhile, intestinal architecture is maintained by downregulation of cell turnover.
Sokolović
Milka
M
AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands. m.sokolovic@amc.uva.nl
Wehkamp
Diederik
D
Sokolović
Aleksandar
A
Vermeulen
Jacqueline
J
Gilhuijs-Pederson
Lisa A
LA
van Haaften
Rachel I M
RI
Nikolsky
Yuri
Y
Evelo
Chris T A
CT
van Kampen
Antoine H C
AH
Hakvoort
Theodorus B M
TB
Lamers
Wouter H
WH
D000222:Adaptation, Physiological; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D050260:Carbohydrate Metabolism; D002453:Cell Cycle; D004579:Electron Transport; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D007421:Intestine, Small / Q000033:anatomy & histology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics
D000596:Amino Acids; D005227:Fatty Acids; D012333:RNA, Messenger