Critical roles for the TSC-mTOR pathway in β-cell function.
TSC1 is a tumor suppressor that associates with TSC2 to inactivate Rheb, thereby inhibiting signaling by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 stimulates cell growth by promoting anabolic cellular processes, such as translation, in response to growth factors and nutrient signals. To test roles for TSC1 and mTORC1 in β-cell function, we utilized Rip2/Cre to generate mice lacking Tsc1 in pancreatic β-cells (Rip-Tsc1cKO mice). Although obesity developed due to hypothalamic Tsc1 excision in older Rip-Tsc1cKO animals, young animals displayed a prominent gain-of-function β-cell phenotype prior to the onset of obesity. The young Rip-Tsc1cKO animals displayed improved glycemic control due to mTOR-mediated enhancement of β-cell size, mass, and insulin production but not determinants of β-cell number (proliferation and apoptosis), consistent with an important anabolic role for mTOR in β-cell function. Furthermore, mTOR mediated these effects in the face of impaired Akt signaling in β-cells. Thus, mTOR promulgates a dominant signal to promote β-cell/islet size and insulin production, and this pathway is crucial for β-cell function and glycemic control.
Mori
Hiroyuki
H
Dept. of Pharmacology and Moores Cancer Center, Univ. of California San Diego, La Jolla, CA 92093-081, USA. kuguan@ucsd.edu
Inoki
Ken
K
Opland
Darren
D
Münzberg
Heike
H
Villanueva
Eneida C
EC
Faouzi
Miro
M
Ikenoue
Tsuneo
T
Kwiatkowski
David J
DJ
Macdougald
Ormond A
OA
Myers
Martin G
MG
Guan
Kun-Liang
KL
D000375:Aging / Q000502:physiology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001066:Appetite / Q000235:genetics / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D048429:Cell Size; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000502:physiology; D009765:Obesity / Q000235:genetics / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D000900:Anti-Bacterial Agents; D001786:Blood Glucose; C519509:Crtc1 protein, mouse; D007328:Insulin; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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