Abstract
Hepatic glucose production (HGP) plays a vital role in maintaining the supply of glucose to the body, and transcription factor FoxO1 is known to confer hormone responsiveness onto HGP. Mice with a liver-specific FoxO1 deletion (L-FoxO1) show reduced HGP and reduced expression of glucose production genes. To determine the contribution of additional transcription factors to HGP, we created double and triple liver-specific knock-outs lacking FoxO1, FoxO3, and FoxO4 or the related protein FoxA2. We show that, when compared with single knock-out of FoxO1, triple ablation of FoxO genes causes more pronounced fasting hypoglycemia, increased glucose tolerance, and enhanced insulin sensitivity, with decreased plasma insulin levels. In contrast, combined ablation of FoxO1 and FoxA2 phenocopied the single knock-out of FoxO1. These data indicate that FoxOs work in concert to regulate multiple aspects of hepatic glucose metabolism.
Highlights
Hepatic glucose production (HGP) plays a vital role in maintaining the supply of glucose to the body, and transcription factor FoxO1 is known to confer hormone responsiveness onto HGP
Hepatic glucose production (HGP)2 is a combination of gluconeogenesis and glycogenolysis, and it is generally accepted that HGP is high in patients with diabetes, the physiology of this abnormality remains disputed [2,3,4]
We have shown that mice with a liver-specific knock-out of FoxO1 (L-FoxO1) display reduced glucogenetic gene expression
Summary
Mice with a liver-specific FoxO1 deletion (L-FoxO1) show reduced HGP and reduced expression of glucose production genes. To determine the contribution of additional transcription factors to HGP, we created double and triple liver-specific knock-outs lacking FoxO1, FoxO3, and FoxO4 or the related protein FoxA2. Combined ablation of FoxO1 and FoxA2 phenocopied the single knock-out of FoxO1 These data indicate that FoxOs work in concert to regulate multiple aspects of hepatic glucose metabolism. L-FoxO1 mice demonstrate that FoxO1 plays a physiological role in the regulation of HGP by hormones It remains unclear whether residual HGP in L-FoxO1 mice reflects non-hormonal (basal) glucose turnover or whether there is another hormoneregulated component that is dependent on additional transcription factors. We found that ablation of all three FoxOs caused considerably greater defects in glucose metabolism, beyond those in L-FoxO1 mice, whereas FoxA2 had no apparent additional effect
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