Essential role of Pten in body size determination and pancreatic beta-cell homeostasis in vivo.
PTEN (phosphatase with tensin homology) is a potent negative regulator of phosphoinositide 3-kinase (PI3K)/Akt signaling, an evolutionarily conserved pathway that signals downstream of growth factors, including insulin and insulin-like growth factor 1. In lower organisms, this pathway participates in fuel metabolism and body size regulation and insulin-like proteins are produced primarily by neuronal structures, whereas in mammals, the major source of insulin is the pancreatic beta cells. Recently, rodent insulin transcription was also shown in the brain, particularly the hypothalamus. The specific regulatory elements of the PI3K pathway in these insulin-expressing tissues that contribute to growth and metabolism in higher organisms are unknown. Here, we report PTEN as a critical determinant of body size and glucose metabolism when targeting is driven by the rat insulin promoter in mice. The partial deletion of PTEN in the hypothalamus resulted in significant whole-body growth restriction and increased insulin sensitivity. Efficient PTEN deletion in beta cells led to increased islet mass without compromise of beta-cell function. Parallel enhancement in PI3K signaling was found in PTEN-deficient hypothalamus and beta cells. Together, we have shown that PTEN in insulin-transcribing cells may play an integrative role in regulating growth and metabolism in vivo.
Nguyen
Kinh-Tung T
KT
Department of Medicine, Medical Biophysics, Institute of Medical Science, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada.
Tajmir
Panteha
P
Lin
Chia Hung
CH
Liadis
Nicole
N
Zhu
Xu-Dong
XD
Eweida
Mohammed
M
Tolasa-Karaman
Gunce
G
Cai
Fang
F
Wang
Rennian
R
Kitamura
Tadahiro
T
Belsham
Denise D
DD
Wheeler
Michael B
MB
Suzuki
Akira
A
Mak
Tak W
TW
Woo
Minna
M
D000818:Animals; D049628:Body Size / Q000235:genetics* / Q000502:physiology; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control; D017353:Gene Deletion; D006706:Homeostasis / Q000235:genetics; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse