FoxO1 as a double-edged sword in the pancreas: analysis of pancreas- and β-cell-specific FoxO1 knockout mice.
Diabetes is characterized by an absolute or relative deficiency of pancreatic β-cells. New strategies to accelerate β-cell neogenesis or maintain existing β-cells are desired for future therapies against diabetes. We previously reported that forkhead box O1 (FoxO1) inhibits β-cell growth through a Pdx1-mediated mechanism. However, we also reported that FoxO1 protects against β-cell failure via the induction of NeuroD and MafA. Here, we investigate the physiological roles of FoxO1 in the pancreas by generating the mice with deletion of FoxO1 in the domains of the Pdx1 promoter (P-FoxO1-KO) or the insulin 2 promoter (β-FoxO1-KO) and analyzing the metabolic parameters and pancreatic morphology under two different conditions of increased metabolic demand: high-fat high-sucrose diet (HFHSD) and db/db background. P-FoxO1-KO, but not β-FoxO1-KO, showed improved glucose tolerance with HFHSD. Immunohistochemical analysis revealed that P-FoxO1-KO had increased β-cell mass due to increased islet number rather than islet size, indicating accelerated β-cell neogenesis. Furthermore, insulin-positive pancreatic duct cells were increased in P-FoxO1-KO but not β-FoxO1-KO. In contrast, db/db mice crossed with P-FoxO1-KO or β-FoxO1-KO showed more severe glucose intolerance than control db/db mice due to decreased glucose-responsive insulin secretion. Electron microscope analysis revealed fewer insulin granules in FoxO1 knockout db/db mice. We conclude that FoxO1 functions as a double-edged sword in the pancreas; FoxO1 essentially inhibits β-cell neogenesis from pancreatic duct cells but is required for the maintenance of insulin secretion under metabolic stress.
Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
Masaki
M
Kobayashi
Osamu
O
Kikuchi
Tsutomu
T
Sasaki
Hye-Jin
HJ
Kim
Hiromi
H
Yokota-Hashimoto
Yong-Soo
YS
Lee
Kosuke
K
Amano
Tomoya
T
Kitazumi
Vina Yanti
VY
Susanti
Yukari Ido
YI
Kitamura
Tadahiro
T
Kitamura
D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D003433:Crosses, Genetic; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D019422:Dietary Sucrose / Q000009:adverse effects; D004195:Disease Models, Animal; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000150:complications / Q000209:etiology / Q000517:prevention & control; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009765:Obesity / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010183:Pancreatic Ducts / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
D019422:Dietary Sucrose; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D012333:RNA, Messenger