Hepatic Suppression of Foxo1 and Foxo3 Causes Hypoglycemia and Hyperlipidemia in Mice

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.

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

“…Previous studies indicate that FOXO1 overexpression in the liver increased hepatic triacylglycerol content, owing to increased triacylglycerol synthesis [40,41], while recent studies suggest that FOXO proteins suppress hepatic lipogenesis and triacylglycerol levels [42,43]. In this study we show that overexpression of FOXQ1 decreases hepatic and serum triacylglycerol contents in db/db and DIO mice.…”

High Glucose Forces a Positive Feedback Loop Connecting Akt Kinase and FoxO1 Transcription Factor to Activate mTORC1 Kinase for Mesangial Cell Hypertrophy and Matrix Protein Expression

“…Using a liver-specific deletion strategy, it has been shown that FoxO1, and not FoxO3/4, reduced blood glucose concentration both in normal and diabetic mice (34). Furthermore, the expression of FoxO1 in different tissues caused insulin resistance and glucose intolerance D) and Ad GFP for 24 h prior to incubation with LG or HG glucose for 24 h. A and C, total RNAs were prepared and used to detect catalase mRNA.…”

Wnt/β-Catenin Signaling Protects Mouse Liver against Oxidative Stress-induced Apoptosis through the Inhibition of Forkhead Transcription Factor FoxO3

“…Immunofluorescence staining of untreated liver tissues revealed a primarily nuclear expression pattern of FoxO3 (Fig. 3, A and D), suggesting that FoxO3 functions physiologically in normal liver homeostasis, probably in its ascribed role of lipid metabolism (40,41). Under oxidative stress, however, FoxO3 mainly translocates to the cytoplasm and membranes (Fig.…”

“…6). Under homeostatic conditions, activation of FoxO3 is required for the control of cellular metabolism, including glycolysis (24) or fatty acid oxidation (40,41). Under oxidative stress, ␤-catenin signaling activates downstream SGK1 in wild-type hepatocytes, which inactivates FoxO3 by phosphorylation, leading to cytoplasmic translocation of FoxO3.…”