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FoxO6 integrates insulin signaling with gluconeogenesis in the liver.

Kim DH, Perdomo G, Zhang T, Slusher S, Lee S, Phillips BE, Fan Y, Giannoukakis N, Gramignoli R, Strom S, Ringquist S, Dong HH - Diabetes (2011)

Bottom Line: This effect stems from inept insulin suppression of hepatic gluconeogenesis.FoxO6 stimulates gluconeogenesis, which is counteracted by insulin.Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. dongh@pitt.edu

ABSTRACT

Objective: Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on hepatic gluconeogenesis and its contribution to glucose metabolism.

Research design and methods: We characterized FoxO6 in glucose metabolism in cultured hepatocytes and in rodent models of dietary obesity, insulin resistance, or insulin-deficient diabetes. We determined the effect of FoxO6 on hepatic gluconeogenesis in genetically modified mice with FoxO6 gain- versus loss-of-function and in diabetic db/db mice with selective FoxO6 ablation in the liver.

Results: FoxO6 integrates insulin signaling to hepatic gluconeogenesis. In mice, elevated FoxO6 activity in the liver augments gluconeogenesis, raising fasting blood glucose levels, and hepatic FoxO6 depletion suppresses gluconeogenesis, resulting in fasting hypoglycemia. FoxO6 stimulates gluconeogenesis, which is counteracted by insulin. Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes. FoxO6 becomes deregulated in the insulin-resistant liver, accounting for its unbridled activity in promoting gluconeogenesis and correlating with the pathogenesis of fasting hyperglycemia in diabetes. These metabolic abnormalities, along with fasting hyperglycemia, are reversible by selective inhibition of hepatic FoxO6 activity in diabetic mice.

Conclusions: Our data uncover a FoxO6-dependent pathway by which the liver orchestrates insulin regulation of gluconeogenesis, providing the proof-of-concept that selective FoxO6 inhibition is beneficial for curbing excessive hepatic glucose production and improving glycemic control in diabetes.

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Effect of FoxO6 transgenic expression on glucose metabolism. FoxO6-CA transgenic (FoxO6-CA-tg) and wild-type littermates were characterized for glucose metabolism. A: Blood glucose levels were determined after a 16-h fast. B: Hepatic PEPCK mRNA levels. C: Hepatic G6Pase mRNA levels. D: Hepatic FoxO6 mRNA levels. E: Blood glucose profiles of glucose tolerance tests (GTT). Mice were fasted for 16 h, followed by glucose injection (2 g/kg i.p. body wt). Blood glucose levels were measured before and after glucose injection. F: Plasma insulin levels were determined after a 16-h fast. G: Body weight. H: Blood glucose profiles of insulin tolerance tests (ITT). Mice were injected with insulin (0.75 IU/kg i.p.), followed by determination of blood glucose levels. I: Blood glucose profiles of pyruvate tolerance tests (PTT). Mice were fasted for 16 h, followed by injection of pyruvate (2 g/kg i.p. body wt). Blood glucose levels were measured before and after pyruvate injection. J: Hepatic G6Pase activity. All data were obtained from male FoxO6-CA-tg mice (n = 8–10) and male age-matched (aged 49–40 weeks) control littermates (n = 5–8). *P < 0.05 and **P < 0.005 vs. control by ANOVA; NS, not significant.
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Figure 6: Effect of FoxO6 transgenic expression on glucose metabolism. FoxO6-CA transgenic (FoxO6-CA-tg) and wild-type littermates were characterized for glucose metabolism. A: Blood glucose levels were determined after a 16-h fast. B: Hepatic PEPCK mRNA levels. C: Hepatic G6Pase mRNA levels. D: Hepatic FoxO6 mRNA levels. E: Blood glucose profiles of glucose tolerance tests (GTT). Mice were fasted for 16 h, followed by glucose injection (2 g/kg i.p. body wt). Blood glucose levels were measured before and after glucose injection. F: Plasma insulin levels were determined after a 16-h fast. G: Body weight. H: Blood glucose profiles of insulin tolerance tests (ITT). Mice were injected with insulin (0.75 IU/kg i.p.), followed by determination of blood glucose levels. I: Blood glucose profiles of pyruvate tolerance tests (PTT). Mice were fasted for 16 h, followed by injection of pyruvate (2 g/kg i.p. body wt). Blood glucose levels were measured before and after pyruvate injection. J: Hepatic G6Pase activity. All data were obtained from male FoxO6-CA-tg mice (n = 8–10) and male age-matched (aged 49–40 weeks) control littermates (n = 5–8). *P < 0.05 and **P < 0.005 vs. control by ANOVA; NS, not significant.

Mentions: To determine the contribution of FoxO6 to glucose metabolism, we generated transgenic mice expressing the constitutively active FoxO6-CA allele from the liver-specific transthyretin promoter. This transgenic line expressed FoxO6-CA specifically in the liver, with nondetectable expression in other peripheral tissues, including pancreatic β-cells (Supplementary Fig. 8). Male FoxO6-CA transgenic mice exhibited significantly higher fasting blood glucose levels compared with control littermates (Fig. 6A). This effect correlated with increased hepatic expression of PEPCK (Fig. 6B), G6Pase (Fig. 6C), and FoxO6 (Fig. 6D) in the livers of FoxO6-CA transgenic mice. FoxO6-CA transgenic mice developed glucose intolerance (Fig. 6E), accompanied by fasting hyperinsulinemia (Fig. 6F). These impaired blood glucose profiles were persistently observed in FoxO6-CA transgenic mice at different ages (Supplementary Fig. 9). No differences in body weights (Fig. 6G) or insulin tolerance tests (Fig. 6H) were detected between FoxO6 transgenic mice and control littermates. Likewise, no significant differences were seen in levels of nonfasting blood glucose, nonfasting plasma insulin, and glucagon between FoxO6 transgenic mice and age- and sex-matched littermate controls (Supplementary Fig. 10). To assess the effect of FoxO6-CA on hepatic gluconeogenesis, we used the pyruvate tolerance test to assess the ability of the liver to convert pyruvate to glucose. FoxO6-CA transgenic mice displayed significantly higher blood glucose levels (Fig. 6I), correlating with elevated G6Pase activity (Fig. 6J). These data indicate that FoxO6 gain-of-function augmented gluconeogenesis in the liver.


FoxO6 integrates insulin signaling with gluconeogenesis in the liver.

Kim DH, Perdomo G, Zhang T, Slusher S, Lee S, Phillips BE, Fan Y, Giannoukakis N, Gramignoli R, Strom S, Ringquist S, Dong HH - Diabetes (2011)

Effect of FoxO6 transgenic expression on glucose metabolism. FoxO6-CA transgenic (FoxO6-CA-tg) and wild-type littermates were characterized for glucose metabolism. A: Blood glucose levels were determined after a 16-h fast. B: Hepatic PEPCK mRNA levels. C: Hepatic G6Pase mRNA levels. D: Hepatic FoxO6 mRNA levels. E: Blood glucose profiles of glucose tolerance tests (GTT). Mice were fasted for 16 h, followed by glucose injection (2 g/kg i.p. body wt). Blood glucose levels were measured before and after glucose injection. F: Plasma insulin levels were determined after a 16-h fast. G: Body weight. H: Blood glucose profiles of insulin tolerance tests (ITT). Mice were injected with insulin (0.75 IU/kg i.p.), followed by determination of blood glucose levels. I: Blood glucose profiles of pyruvate tolerance tests (PTT). Mice were fasted for 16 h, followed by injection of pyruvate (2 g/kg i.p. body wt). Blood glucose levels were measured before and after pyruvate injection. J: Hepatic G6Pase activity. All data were obtained from male FoxO6-CA-tg mice (n = 8–10) and male age-matched (aged 49–40 weeks) control littermates (n = 5–8). *P < 0.05 and **P < 0.005 vs. control by ANOVA; NS, not significant.
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Figure 6: Effect of FoxO6 transgenic expression on glucose metabolism. FoxO6-CA transgenic (FoxO6-CA-tg) and wild-type littermates were characterized for glucose metabolism. A: Blood glucose levels were determined after a 16-h fast. B: Hepatic PEPCK mRNA levels. C: Hepatic G6Pase mRNA levels. D: Hepatic FoxO6 mRNA levels. E: Blood glucose profiles of glucose tolerance tests (GTT). Mice were fasted for 16 h, followed by glucose injection (2 g/kg i.p. body wt). Blood glucose levels were measured before and after glucose injection. F: Plasma insulin levels were determined after a 16-h fast. G: Body weight. H: Blood glucose profiles of insulin tolerance tests (ITT). Mice were injected with insulin (0.75 IU/kg i.p.), followed by determination of blood glucose levels. I: Blood glucose profiles of pyruvate tolerance tests (PTT). Mice were fasted for 16 h, followed by injection of pyruvate (2 g/kg i.p. body wt). Blood glucose levels were measured before and after pyruvate injection. J: Hepatic G6Pase activity. All data were obtained from male FoxO6-CA-tg mice (n = 8–10) and male age-matched (aged 49–40 weeks) control littermates (n = 5–8). *P < 0.05 and **P < 0.005 vs. control by ANOVA; NS, not significant.
Mentions: To determine the contribution of FoxO6 to glucose metabolism, we generated transgenic mice expressing the constitutively active FoxO6-CA allele from the liver-specific transthyretin promoter. This transgenic line expressed FoxO6-CA specifically in the liver, with nondetectable expression in other peripheral tissues, including pancreatic β-cells (Supplementary Fig. 8). Male FoxO6-CA transgenic mice exhibited significantly higher fasting blood glucose levels compared with control littermates (Fig. 6A). This effect correlated with increased hepatic expression of PEPCK (Fig. 6B), G6Pase (Fig. 6C), and FoxO6 (Fig. 6D) in the livers of FoxO6-CA transgenic mice. FoxO6-CA transgenic mice developed glucose intolerance (Fig. 6E), accompanied by fasting hyperinsulinemia (Fig. 6F). These impaired blood glucose profiles were persistently observed in FoxO6-CA transgenic mice at different ages (Supplementary Fig. 9). No differences in body weights (Fig. 6G) or insulin tolerance tests (Fig. 6H) were detected between FoxO6 transgenic mice and control littermates. Likewise, no significant differences were seen in levels of nonfasting blood glucose, nonfasting plasma insulin, and glucagon between FoxO6 transgenic mice and age- and sex-matched littermate controls (Supplementary Fig. 10). To assess the effect of FoxO6-CA on hepatic gluconeogenesis, we used the pyruvate tolerance test to assess the ability of the liver to convert pyruvate to glucose. FoxO6-CA transgenic mice displayed significantly higher blood glucose levels (Fig. 6I), correlating with elevated G6Pase activity (Fig. 6J). These data indicate that FoxO6 gain-of-function augmented gluconeogenesis in the liver.

Bottom Line: This effect stems from inept insulin suppression of hepatic gluconeogenesis.FoxO6 stimulates gluconeogenesis, which is counteracted by insulin.Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. dongh@pitt.edu

ABSTRACT

Objective: Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on hepatic gluconeogenesis and its contribution to glucose metabolism.

Research design and methods: We characterized FoxO6 in glucose metabolism in cultured hepatocytes and in rodent models of dietary obesity, insulin resistance, or insulin-deficient diabetes. We determined the effect of FoxO6 on hepatic gluconeogenesis in genetically modified mice with FoxO6 gain- versus loss-of-function and in diabetic db/db mice with selective FoxO6 ablation in the liver.

Results: FoxO6 integrates insulin signaling to hepatic gluconeogenesis. In mice, elevated FoxO6 activity in the liver augments gluconeogenesis, raising fasting blood glucose levels, and hepatic FoxO6 depletion suppresses gluconeogenesis, resulting in fasting hypoglycemia. FoxO6 stimulates gluconeogenesis, which is counteracted by insulin. Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes. FoxO6 becomes deregulated in the insulin-resistant liver, accounting for its unbridled activity in promoting gluconeogenesis and correlating with the pathogenesis of fasting hyperglycemia in diabetes. These metabolic abnormalities, along with fasting hyperglycemia, are reversible by selective inhibition of hepatic FoxO6 activity in diabetic mice.

Conclusions: Our data uncover a FoxO6-dependent pathway by which the liver orchestrates insulin regulation of gluconeogenesis, providing the proof-of-concept that selective FoxO6 inhibition is beneficial for curbing excessive hepatic glucose production and improving glycemic control in diabetes.

Show MeSH
Related in: MedlinePlus