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Single-cell Transcriptomic Analyses of Mouse Pancreatic Endocrine Cells
Published on: September 30, 2018
FoxO1 as a double-edged sword in the pancreas: analysis of pancreas- and β-cell-specific FoxO1 knockout mice
Masaki Kobayashi1, Osamu Kikuchi, Tsutomu Sasaki
1Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
Abstract:
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.
Insights
Forkhead box O1 (FoxO1) plays a dual role in diabetes research. It inhibits new beta-cell formation but is crucial for maintaining insulin secretion under metabolic stress.
Area of Science:
- Endocrinology
- Metabolic diseases
- Molecular biology
Background:
- Diabetes mellitus is a metabolic disorder characterized by pancreatic beta-cell deficiency.
- Forkhead box O1 (FoxO1) has contradictory roles in beta-cell function, inhibiting growth yet protecting against failure.
- Understanding FoxO1's precise functions is critical for developing novel diabetes therapies.
Purpose of the Study:
- To elucidate the physiological roles of FoxO1 in pancreatic beta-cell neogenesis and function.
- To investigate FoxO1's impact on metabolic parameters and pancreatic morphology under metabolic stress.
- To differentiate the roles of FoxO1 regulated by the Pdx1 and insulin 2 promoters.
Main Methods:
- Generation of mice with FoxO1 deletion under the Pdx1 promoter (P-FoxO1-KO) and insulin 2 promoter (β-FoxO1-KO).
- Analysis of metabolic parameters and pancreatic morphology in mice fed a high-fat high-sucrose diet (HFHSD) or on a db/db background.
- Immunohistochemistry and electron microscopy to assess beta-cell mass, islet number, and insulin granule content.
Main Results:
- P-FoxO1-KO mice exhibited improved glucose tolerance on HFHSD, linked to increased beta-cell neogenesis and more insulin-positive duct cells.
- Neither P-FoxO1-KO nor β-FoxO1-KO improved glucose intolerance in db/db mice; instead, they showed exacerbated hyperglycemia.
- FoxO1 knockout in db/db mice led to reduced insulin secretion and fewer insulin granules, indicating impaired function under metabolic stress.
Conclusions:
- FoxO1 acts as a double-edged sword: it inhibits beta-cell neogenesis from pancreatic duct cells but is essential for maintaining insulin secretion capacity during metabolic stress.
- Targeting FoxO1 requires a nuanced approach, considering its opposing roles in beta-cell proliferation and function.
- These findings offer insights into potential therapeutic strategies for diabetes by modulating FoxO1 activity.
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