Molecular mechanisms of pancreatic dysfunction induced by protein malnutrition.
OBJECTIVE
Dietary protein deficiency results in diminished capacity of the pancreas to secrete enzymes needed for macronutrient digestion. Previous work has suggested that modulation of the mammalian target of rapamycin (mTOR) pathway by the hormone cholecystokinin (CCK) plays an important role in normal digestive enzyme synthesis after feeding. The purpose of this study was to elucidate the role of mTOR in protein deficiency-induced pancreatic dysfunction.


METHODS
Wild-type and CCK-null mice were fed protein-deficient chow for 4 days and then allowed to recover on control chow in the presence or absence of the mTOR inhibitor rapamycin.


RESULTS
The size and secretory capacity of the pancreas rapidly decreased after feeding protein-deficient chow. Refeeding protein-replete chow reversed these changes in both wild-type and CCK-null mice. Changes in the size of the pancreas were paralleled by changes in the content and secretion of digestive enzymes, as well as the phosphorylation of downstream targets of mTOR. Administration of the mTOR inhibitor rapamycin decreased regrowth of the pancreas but did not affect digestive enzyme content or secretory capacity.


CONCLUSIONS
These studies demonstrate that dietary protein modulates pancreatic growth, but not digestive enzyme synthesis, via CCK-independent activation of the mTOR pathway.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5622, USA. scrozier@umich.edu
Stephen J
SJ
Crozier
Louis G
LG
D'Alecy
Stephen A
SA
Ernst
Lauren E
LE
Ginsburg
John A
JA
Williams
D000818:Animals; D001284:Atrophy; D002352:Carrier Proteins / Q000378:metabolism; D002766:Cholecystokinin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D010179:Pancreas / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011488:Protein Deficiency / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; D002766:Cholecystokinin; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus