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Deletion of hepatic FoxO1/3/4 genes in mice significantly impacts on glucose metabolism through downregulation of gluconeogenesis and upregulation of glycolysis.

Xiong X, Tao R, DePinho RA, Dong XC - PLoS ONE (2013)

Bottom Line: With regard to glucose metabolism, most studies have been focused on FoxO1.To understand the underlying mechanisms, we examined the roles of SIRT6 (Sirtuin 6) and Gck (glucokinase) in the FoxO-mediated glucose metabolism.Collectively, FoxO1/3/4 transcription factors play important roles in hepatic glucose homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.

ABSTRACT
Forkhead transcription factors FoxO1/3/4 have pleiotrophic functions including anti-oxidative stress and metabolism. With regard to glucose metabolism, most studies have been focused on FoxO1. To further investigate their hepatic functions, we generated liver-specific FoxO1/3/4 knockout mice (LTKO) and examined their collective impacts on glucose homeostasis under physiological and pathological conditions. As compared to wild-type mice, LTKO mice had lower blood glucose levels under both fasting and non-fasting conditions and they manifested better glucose and pyruvate tolerance on regular chow diet. After challenged by a high-fat diet, wild-type mice developed type 2 diabetes, but LTKO mice remained euglycemic and insulin-sensitive. To understand the underlying mechanisms, we examined the roles of SIRT6 (Sirtuin 6) and Gck (glucokinase) in the FoxO-mediated glucose metabolism. Interestingly, ectopic expression of SIRT6 in the liver only reduced gluconeogenesis in wild-type but not LTKO mice whereas knockdown of Gck caused glucose intolerance in both wild-type and LTKO mice. The data suggest that both decreased gluconeogenesis and increased glycolysis may contribute to the overall glucose phenotype in the LTKO mice. Collectively, FoxO1/3/4 transcription factors play important roles in hepatic glucose homeostasis.

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Related in: MedlinePlus

Gck knockdown impairs glucose tolerance in both wild-type and LTKO mice.(A) Gck protein was analyzed in the livers of 3-month-old control and LTKO mice by Western blots. (B) Gck knockdown was assessed by Western blots in liver lysates from control and LTKO mice injected with shGck or shGFP adenoviruses. (C, D) Glucose tolerance tests and insulin tolerance tests in 6-month-old male control and LTKO mice injected with shGck or shGFP adenoviruses (n=5-6), respectively. Data represent mean ± SEM. *, P<0.05 between LTKO-shGFP and LTKO-shGck groups; #, P<0.05 between loxp-shGFP and loxp-shGck groups.
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pone-0074340-g007: Gck knockdown impairs glucose tolerance in both wild-type and LTKO mice.(A) Gck protein was analyzed in the livers of 3-month-old control and LTKO mice by Western blots. (B) Gck knockdown was assessed by Western blots in liver lysates from control and LTKO mice injected with shGck or shGFP adenoviruses. (C, D) Glucose tolerance tests and insulin tolerance tests in 6-month-old male control and LTKO mice injected with shGck or shGFP adenoviruses (n=5-6), respectively. Data represent mean ± SEM. *, P<0.05 between LTKO-shGFP and LTKO-shGck groups; #, P<0.05 between loxp-shGFP and loxp-shGck groups.

Mentions: In addition to gluconeogenesis, FoxOs have been implicated in glycolysis in the liver [12,16,17,25–27]. Indeed, Western blot analysis showed that Gck protein was increased more than 2-fold in the LTKO livers (Figure 7A). To test the extent of the elevated Gck expression to glucose metabolism in LTKO mice, we knocked down hepatic Gck gene using adenovirus-mediated shRNAs (Figure 7B). Seven days post-injection, we performed glucose tolerance tests, and the results showed that knockdown of the Gck gene led to glucose intolerance in both wild-type and LTKO mice (Figure 7C). Two days later, we also performed insulin tolerance tests. No difference was observed regardless of genotypes or gene knockdown (Figure 7D). These data suggest that Gck mediated hepatic glycolysis also plays a significant role in FoxOs-regulated glucose metabolism.


Deletion of hepatic FoxO1/3/4 genes in mice significantly impacts on glucose metabolism through downregulation of gluconeogenesis and upregulation of glycolysis.

Xiong X, Tao R, DePinho RA, Dong XC - PLoS ONE (2013)

Gck knockdown impairs glucose tolerance in both wild-type and LTKO mice.(A) Gck protein was analyzed in the livers of 3-month-old control and LTKO mice by Western blots. (B) Gck knockdown was assessed by Western blots in liver lysates from control and LTKO mice injected with shGck or shGFP adenoviruses. (C, D) Glucose tolerance tests and insulin tolerance tests in 6-month-old male control and LTKO mice injected with shGck or shGFP adenoviruses (n=5-6), respectively. Data represent mean ± SEM. *, P<0.05 between LTKO-shGFP and LTKO-shGck groups; #, P<0.05 between loxp-shGFP and loxp-shGck groups.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3755981&req=5

pone-0074340-g007: Gck knockdown impairs glucose tolerance in both wild-type and LTKO mice.(A) Gck protein was analyzed in the livers of 3-month-old control and LTKO mice by Western blots. (B) Gck knockdown was assessed by Western blots in liver lysates from control and LTKO mice injected with shGck or shGFP adenoviruses. (C, D) Glucose tolerance tests and insulin tolerance tests in 6-month-old male control and LTKO mice injected with shGck or shGFP adenoviruses (n=5-6), respectively. Data represent mean ± SEM. *, P<0.05 between LTKO-shGFP and LTKO-shGck groups; #, P<0.05 between loxp-shGFP and loxp-shGck groups.
Mentions: In addition to gluconeogenesis, FoxOs have been implicated in glycolysis in the liver [12,16,17,25–27]. Indeed, Western blot analysis showed that Gck protein was increased more than 2-fold in the LTKO livers (Figure 7A). To test the extent of the elevated Gck expression to glucose metabolism in LTKO mice, we knocked down hepatic Gck gene using adenovirus-mediated shRNAs (Figure 7B). Seven days post-injection, we performed glucose tolerance tests, and the results showed that knockdown of the Gck gene led to glucose intolerance in both wild-type and LTKO mice (Figure 7C). Two days later, we also performed insulin tolerance tests. No difference was observed regardless of genotypes or gene knockdown (Figure 7D). These data suggest that Gck mediated hepatic glycolysis also plays a significant role in FoxOs-regulated glucose metabolism.

Bottom Line: With regard to glucose metabolism, most studies have been focused on FoxO1.To understand the underlying mechanisms, we examined the roles of SIRT6 (Sirtuin 6) and Gck (glucokinase) in the FoxO-mediated glucose metabolism.Collectively, FoxO1/3/4 transcription factors play important roles in hepatic glucose homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.

ABSTRACT
Forkhead transcription factors FoxO1/3/4 have pleiotrophic functions including anti-oxidative stress and metabolism. With regard to glucose metabolism, most studies have been focused on FoxO1. To further investigate their hepatic functions, we generated liver-specific FoxO1/3/4 knockout mice (LTKO) and examined their collective impacts on glucose homeostasis under physiological and pathological conditions. As compared to wild-type mice, LTKO mice had lower blood glucose levels under both fasting and non-fasting conditions and they manifested better glucose and pyruvate tolerance on regular chow diet. After challenged by a high-fat diet, wild-type mice developed type 2 diabetes, but LTKO mice remained euglycemic and insulin-sensitive. To understand the underlying mechanisms, we examined the roles of SIRT6 (Sirtuin 6) and Gck (glucokinase) in the FoxO-mediated glucose metabolism. Interestingly, ectopic expression of SIRT6 in the liver only reduced gluconeogenesis in wild-type but not LTKO mice whereas knockdown of Gck caused glucose intolerance in both wild-type and LTKO mice. The data suggest that both decreased gluconeogenesis and increased glycolysis may contribute to the overall glucose phenotype in the LTKO mice. Collectively, FoxO1/3/4 transcription factors play important roles in hepatic glucose homeostasis.

Show MeSH
Related in: MedlinePlus