CCK-independent mTORC1 activation during dietary protein-induced exocrine pancreas growth.
Dietary protein can stimulate pancreatic growth in the absence of CCK release, but there is little data on the regulation of CCK-independent growth. To identify mechanisms whereby protein stimulates pancreatic growth in the absence of CCK release, C57BL/6 control and CCK-null male mice were fed normal-protein (14% casein) or high-protein (75% casein) chow for 7 days. The weight of the pancreas increased by 32% in C57BL/6 mice and 26% in CCK-null mice fed high-protein chow. Changes in pancreatic weight in control mice were due to both cell hypertrophy and hyperplasia since there was an increase in protein-to-DNA ratio, total DNA content, and DNA synthesis. In CCK-null mice pancreatic growth was almost entirely due to hypertrophy with both protein-to-DNA ratio and cell size increasing without significant increases in DNA content or DNA synthesis. ERK, calcineurin, and mammalian target of rapamycin complex 1 (mTORC1) are activated in models of CCK-induced growth, but there were no differences in ERK or calcineurin activation between fasted and fed CCK-null mice. In contrast, mTORC1 activation was increased after feeding and the duration of activation was prolonged in mice fed high-protein chow compared with normal-protein chow. Changes in pancreatic weight and RNA content were completely inhibited, and changes in protein content were partially abated, when the mTORC1 inhibitor rapamycin was administered during high-protein chow feeding. Prolonged mTORC1 activation is thus required for dietary protein-induced pancreatic growth in the absence of CCK.
Crozier
Stephen J
SJ
Department of 1Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Sans
M Dolors
MD
Wang
Jackie Y
JY
Lentz
Stephen I
SI
Ernst
Stephen A
SA
Williams
John A
JA
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D002766:Cholecystokinin / Q000235:genetics / Q000378:metabolism*; D004044:Dietary Proteins / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D009929:Organ Size; D046790:Pancreas, Exocrine / Q000254:growth & development* / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*
D004044:Dietary Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D002766:Cholecystokinin; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin
Pancreas. 1992;7(5):522-9
1381095
J Nutr. 2006 Jul;136(7):1792-9
16772439
Cell Metab. 2008 Nov;8(5):399-410
19046571
Am J Physiol Cell Physiol. 2005 Dec;289(6):C1457-65
16079186
J Biol Chem. 1998 Aug 28;273(35):22738-44
9712905
J Nutr. 1995 May;125(5):1143-9
7738673
Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1148-57
18356533
J Nutr. 2005 Mar;135(3):376-82
15735066
Nat Rev Cancer. 2006 Sep;6(9):729-34
16915295
Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E592-602
18765678
Eur J Biochem. 1994 Jan 15;219(1-2):109-17
7508382
Am J Physiol. 1997 Nov;273(5):C1472-9
9374631
J Gastroenterol. 2003;38(7):672-80
12898360
Pancreas. 2006 Apr;32(3):314-20
16628088
Gut. 1987;28 Suppl:63-9
2446964
Am J Physiol. 1986 Aug;251(2 Pt 1):G243-8
3740265
Am J Physiol. 1999 May;276(5):G1302-9
10330022
Am J Physiol. 1986 Oct;251(4 Pt 1):G487-94
3020992
Proc Soc Exp Biol Med. 1976 Dec;153(3):523-7
1013167
J Physiol. 2006 Jun 15;573(Pt 3):775-86
16613881
Endocrinology. 1980 Jan;106(1):323-8
7349962
Fed Proc. 1963 Jul-Aug;22:1122-5
14046290
Am J Physiol. 1986 Jul;251(1 Pt 1):G70-4
3524262
Am J Physiol. 1992 Apr;262(4 Pt 1):G740-6
1373568
Autophagy. 2007 May-Jun;3(3):181-206
17224625
Pancreas. 1986;1(6):509-15
3562444
Mol Biol Cell. 2008 Jan;19(1):198-206
17978097
Trends Cell Biol. 2009 Jun;19(6):260-7
19419870
Int J Gastrointest Cancer. 2002;31(1-3):107-15
12622421
Am J Physiol. 1984 Dec;247(6 Pt 1):G611-6
6507618
Curr Opin Cell Biol. 2005 Apr;17(2):158-66
15780592
J Biol Chem. 2009 Mar 20;284(12):8023-32
19150980
Am J Physiol. 1997 Jul;273(1 Pt 1):C101-9
9252447
Am J Physiol. 1968 May;214(5):1008-13
5647177
Cell Metab. 2008 Nov;8(5):411-24
19046572
Gastroenterology. 2009 Sep;137(3):1093-101, 1101.e1-3
19427311
Am J Physiol Gastrointest Liver Physiol. 2004 May;286(5):G784-90
14684381