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Published on: September 9, 2021
Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice
Kebin Zhang1, Ling Li, Yajuan Qi
1Division of Molecular Cardiology, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, Central Texas Veterans Health Care System, Temple, Texas 76504, USA.
Abstract:
Dysregulation of blood glucose and triglycerides are the major characteristics of type 2 diabetes mellitus. We sought to identify the mechanisms regulating blood glucose and lipid homeostasis. Cell-based studies established that the Foxo forkhead transcription factors Forkhead box O (Foxo)-1, Foxo3, and Foxo4 are inactivated by insulin via a phosphatidylinositol 3-kinase/Akt-dependent pathway, but the role of Foxo transcription factors in the liver in regulating nutrient metabolism is incompletely understood. In this study, we used the Cre/LoxP genetic approach to delete the Foxo1, Foxo3, and Foxo4 genes individually or a combination of two or all in the liver of lean or db/db mice and assessed the role of Foxo inactivation in regulating glucose and lipid homeostasis in vivo. In the lean mice or db/db mice, hepatic deletion of Foxo1, rather than Foxo3 or Foxo4, caused a modest reduction in blood glucose concentrations and barely affected lipid homeostasis. Combined deletion of Foxo1 and Foxo3 decreased blood glucose levels, elevated serum triglyceride and cholesterol concentrations, and increased hepatic lipid secretion and caused hepatosteatosis. Analysis of the liver transcripts established a prominent role of Foxo1 in regulating gene expression of gluconeogenic enzymes and Foxo3 in the expression of lipogenic enzymes. Our findings indicate that Foxo1 and Foxo3 inactivation serves as a potential mechanism by which insulin reduces hepatic glucose production and increases hepatic lipid synthesis and secretion in healthy and diabetic states.
Insights
Forkhead box O (Foxo) transcription factors regulate nutrient metabolism. Inactivating Foxo1 and Foxo3 in the liver impacts blood glucose and lipid homeostasis, offering insights into diabetes management.
Area of Science:
- Metabolic Regulation
- Molecular Biology
- Genetics
Background:
- Type 2 diabetes mellitus is characterized by dysregulated blood glucose and triglycerides.
- Insulin inactivates Forkhead box O (Foxo) transcription factors (Foxo1, Foxo3, Foxo4) via the PI3K/Akt pathway.
- The role of hepatic Foxo transcription factors in nutrient metabolism requires further elucidation.
Purpose of the Study:
- To investigate the in vivo role of hepatic Foxo transcription factors (Foxo1, Foxo3, Foxo4) in regulating glucose and lipid homeostasis.
- To determine the specific contributions of Foxo1, Foxo3, and Foxo4 to nutrient metabolism in lean and diabetic mouse models.
Main Methods:
- Utilized the Cre/LoxP genetic system for targeted deletion of Foxo1, Foxo3, and Foxo4 genes in the liver of lean and db/db mice.
- Assessed the impact of individual and combined Foxo gene deletions on blood glucose, triglyceride, and cholesterol levels.
- Analyzed liver gene expression profiles to identify Foxo-regulated metabolic pathways.
Main Results:
- Hepatic deletion of Foxo1 alone modestly reduced blood glucose levels with minimal impact on lipid homeostasis.
- Combined deletion of Foxo1 and Foxo3 significantly decreased blood glucose, elevated serum lipids, increased hepatic lipid secretion, and induced hepatosteatosis.
- Foxo1 primarily regulates gluconeogenic enzyme gene expression, while Foxo3 is crucial for lipogenic enzyme expression.
Conclusions:
- Hepatic Foxo1 inactivation contributes to reduced glucose production, while Foxo3 inactivation influences lipid synthesis and secretion.
- Foxo1 and Foxo3 inactivation represent potential mechanisms underlying insulin's regulation of hepatic glucose and lipid metabolism in both healthy and diabetic states.
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