Insulin Inhibits the Activation of Transcription by a C-terminal Fragment of the Forkhead Transcription Factor FKHR

Tomizawa, M.; Kumar, Amit; Perrot, Valérie; Nakae, Jun; Accili, Domenico; Rechler, Matthew M.

doi:10.1074/jbc.275.10.7289

Cited by 64 publications

(67 citation statements)

References 61 publications

(62 reference statements)

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“…One of the hepatic actions of insulin, working via activation of the Akt kinase, is to Ser/Thr phosphorylate and inactivate forkhead transcription factor(s). Of particular importance for this discussion, forkhead rhabdomyosarcoma transcription factor (FKHR) is a major regulator of IGFBP-1 mRNA (20,42,50,53,54). Nonphosphorylated FKHR in the nucleus activates IGFBP-1 transcription.…”

Section: Discussionmentioning

confidence: 99%

Hemorrhage induces the rapid development of hepatic insulin resistance

Wang

Kuebler

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hyperglycemia is an early metabolic response to trauma and hemorrhage. The role of hepatic insulin resistance to the development of this hyperglycemia is not well understood. The aim of this study was to determine whether the liver becomes insulin resistant and to identify the particular hepatic insulin signaling pathways that may be compromised following trauma and hemorrhage. Male adult rats were bled to a mean arterial pressure of 40 mmHg and maintained at that pressure for 90 min followed by resuscitation with Ringer lactate. Data showed that trauma and hemorrhage rapidly induced profound hyperinsulinemia in combination with significant hyperglycemia, suggesting the development of insulin resistance. After trauma and hemorrhage, hepatic insulin signaling via the insulin-induced phosphatidylinositol 3 (PI3)-kinase-Akt pathway was abolished, whereas ERK1/2 signaling was relatively normal. The regulation (inhibition) of a hepatic-, insulin-, and the PI3-kinase-dependent gene, IGF binding protein-1, was also lost. The present study provides convincing evidence of a rapid onset hepatic insulin resistance following a combination of trauma and hemorrhage.

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Section: Discussionmentioning

confidence: 99%

Hemorrhage induces the rapid development of hepatic insulin resistance

Wang

Kuebler

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…However, we have now shown that renal IGFBP1 is also increased in our model of type 2 diabetes mellitus, where circulating GH is decreased and hyperinsulinaemia has been described [26]. This potential contradiction may be explained by recently discovered pathways of insulin resistance involving the downregulation of the transcription factor FOXO1 [27], a known insulin-controlled positive regulator of IGFBP1 transcription [28]. Insulin inhibits FOXO1 activity by phosphorylating it via v-akt murine thymoma viral oncogene homologue 1 (AKT1), thus preventing its entrance into the nucleus.…”

Section: Discussionmentioning

confidence: 69%

Systemic and renal growth hormone–IGF1 axis involvement in a mouse model of type 2 diabetes

et al. 2007

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Aims/hypothesis In previous studies we have shown a significant involvement of the growth hormone (GH)-IGF axis in animal models of type 1 diabetes mellitus, but the role of this endocrine system in type 2 diabetes mellitus is less well characterised. We therefore examined the endocrine and renal GH-IGF axis changes in db/db mice, a model of type 2 diabetes mellitus and nephropathy. Materials and methods Obese and lean animals were followed, beginning at hyperglycaemia onset, for 4 weeks. Albuminuria and creatinine clearance, as well as kidney and glomerular morphology were assessed. Tissue protein levels were determined by western blotting and mRNA levels by RT-PCR.Results Serum GH and IGF1 levels immediately prior to killing were decreased and liver mRNA levels of insulinlike growth factor binding protein 1 (Igfbp1) were increased in obese animals. Kidney weight was increased in obese animals, associated with hyperfiltration, albuminuria and glomerular hypertrophy. Administration of a somatostatin analogue (PTR-313) did not improve any of these parameters of diabetic renal involvement. Renal Igf1 mRNA was decreased and renal Igfbp1 mRNA and protein were significantly increased in obese animals. Renal insulindriven levels of phosphorylated forkhead box O1 (FOXO1) were decreased in obese animals. Conclusions/interpretation Diabetic db/db mice show significant renal changes (and IGFBP1 renal accumulation), similar to the findings in models of type 1 diabetes mellitus. A decreased signalling through the insulin receptor and decreased FOXO1 phosphorylation may allow Igfbp1 gene transcription. These renal changes are associated with low circulating IGF1 and GH levels and unchanged hepatic growth hormone receptor expression, unlike the condition in type 1 diabetes mellitus. This suggests that further GH inhibition to modulate renal complications in type 2 diabetes mellitus is not indicated.

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“…The carboxyl domain of Foxo1, when fused to a heterologous Gal4 DNA-binding domain, can stimulate Gal4 promoter activity in an insulin-responsive manner (31). In contrast, the amino domain of Foxo1 (designated Foxo1-⌬256) has been shown to act as a dominant negative mutant to inhibit PEPCK and G-6-Pase expression in cultured cells (21).…”

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confidence: 99%

“…Using the IGFBP-1 promoter-directed expression system, the forkhead transcription factor Foxo1 (or FKHR) has been shown to play an important role in mediating insulin action and regulating target gene expression (13,14,19,21,22). In the absence of insulin, Foxo1 binds to IRE in target promoters and stimulates the promoter activity (1,13,31). In response to insulin, Foxo1 undergoes phosphatidylinositol (PI) 3-kinase-dependent phosphorylation and is excluded from the nucleus, resulting in inhibition of Foxo1-dependent transcription (2,5,6,13,22,27).…”

mentioning

confidence: 99%

“…Foxo1 comprises two structural domains, the amino domain, which is responsible for DNA binding to target promoters, and the carboxyl transactivation domain, which functions to stimulate promoter activity (19,31). The carboxyl domain of Foxo1, when fused to a heterologous Gal4 DNA-binding domain, can stimulate Gal4 promoter activity in an insulin-responsive manner (31).…”

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confidence: 99%

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Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice

Altomonte

Richter²,

Harbaran³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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185

184

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Excessive hepatic glucose production is a contributing factor to fasting hyperglycemia in diabetes. Insulin suppresses hepatic glucose production by inhibiting the expression of two gluconeogenic enzymes, phospho enolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase). The forkhead transcription factor Foxo1 has been implicated as a mediator of insulin action in regulating hepatic gluconeogenesis, and a Foxo1 mutant (Foxo1-Δ256), devoid of its carboxyl domain, has been shown to interfere with Foxo1 function and inhibit gluconeogenic gene expression in cultured cells. To study the effect of Foxo1-Δ256 on glucose metabolism in animals, the Foxo1-Δ256 cDNA was delivered to the livers of mice by adenovirus-mediated gene transfer. Hepatic Foxo1-Δ256 production resulted in inhibition of gluconeogenic activity, as evidenced by reduced PEPCK and G-6-Pase expression in the liver. Mice treated with the Foxo1-Δ256 vector exhibited significantly reduced blood glucose levels. In contrast, blood glucose levels in control vector-treated animals remained unchanged, which coincided with the lack of alterations in the expression levels of PEPCK and G-6-Pase. When tested in diabetic db/db mice, hepatic production of Foxo1-Δ256 was shown to reduce fasting hyperglycemia. Furthermore, we showed that hepatic Foxo1 expression was deregulated as a result of insulin resistance in diabetic mice and that Foxo1-Δ256 interfered with Foxo1 function via competitive binding to target promoters. These results demonstrated that functional inhibition of Foxo1, caused by hepatic expression of its mutant, is associated with reduced hepatic gluconeogenic activity and improved fasting glycemia in diabetic mice.

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Insulin Inhibits the Activation of Transcription by a C-terminal Fragment of the Forkhead Transcription Factor FKHR

Cited by 64 publications

References 61 publications

Hemorrhage induces the rapid development of hepatic insulin resistance

Hemorrhage induces the rapid development of hepatic insulin resistance

Systemic and renal growth hormone–IGF1 axis involvement in a mouse model of type 2 diabetes

Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice

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