Insulin-Regulated Gene Expression

O'Brien, RM; Streeper, Ryan S.; Stadelmaier, B. T.; Hornbuckle, Lauri A.

doi:10.1042/bst029a061b

Cited by 49 publications

(68 citation statements)

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“…These genes share a consensus IRE sequence in their respective promoters (24). This highly conserved IRE DNA element serves as a target site of Foxo1 in mediating insulin action.…”

Section: Discussionmentioning

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

186

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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“…These genes share a consensus IRE sequence in their respective promoters (24). This highly conserved IRE DNA element serves as a target site of Foxo1 in mediating insulin action.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have characterized Foxo1 as a mediator of insulin action in controlling the expression of genes that are downregulated by insulin (17,24).…”

Section: Discussionmentioning

confidence: 99%

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

186

184

View full text Add to dashboard Cite

show abstract

“…Lymphoblastic thymic lymphoma Hemangioma [65,66] FoxO1 is highly expressed in developing embryonic vasculature. FoxO1 has a crucial role in vascular formation [60].…”

Section: Foxo1 Knockout Micementioning

confidence: 99%

“…In mammalians, at CR or food-deprivation state, hepatic glucose production is increased and glucose is supplied to brain where glucose is an only source of energy. Genes that are involved in gluconeogenesis, which include glucose 6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase (Pck1), are upregulated at fasting, insulin deficient or insulin resistant state and downregulated at fed state or by insulin [65,66]. The promoter regions of these two genes have the insulin-responsive elements (IREs) with a T(G/ A)TTT(T/G)(G/T) core sequence, which is quite similar to FoxO-responsive elements (FREs).…”

Section: Livermentioning

confidence: 99%

The FoxO transcription factors and metabolic regulation

2007

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Forkhead transcription factors FoxOs are conserved beyond species and regulated by insulin signaling pathway. FoxOs have diverse functions on differentiation, proliferation and cell survival. In calorie restriction (CR) or starvation, FoxOs are in nucleus, active transcriptionally, and increase hepatic glucose production, decrease insulin secretion, increase food intake and cause degradation of skeletal muscle for supplying substrates for glucose production. However, even in insulin resistance due to excessive calorie intake, FoxOs are active and causes type 2 diabetes and hyperlipidemia. The understanding of molecular mechanism how FoxOs affect glucose or lipid metabolism will shed light on the novel therapy of type 2 diabetes and the metabolic syndrome.

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“…It can modulate intracellular metabolism by altering the activity or intracellular location of various enzymes, and it can regulate gene expression. More than 150 insulin-responsive genes are known [9][10][11], and these encode proteins related to various cellular functions. The specific insulin response depends on the type and stage of differentiation of the cell.…”

Section: Introductionmentioning

confidence: 99%

Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy

et al. 2005

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Aims/hypothesis: The human placenta is a complex organ situated at the interface between mother and foetus that separates maternal from foetal blood. The placental surfaces exposed to the two bloodstreams are different, i.e. trophoblasts and endothelial cells are in contact with the maternal and foetal circulation, respectively. Both cell types produce high insulin receptor levels. The aim of the present study was to test the hypothesis that spatiotemporal changes in insulin receptor expression in trophoblasts from first trimester to the endothelium at term shift the control of insulin-dependent processes from mother to foetus. Methods: Global microarray analysis of primary trophoblasts from first trimester and term human placentas and endothelial cells from term human placentas cultured under hyperinsulinaemic and control conditions identified different sets of regulated genes in trophoblasts and endothelial cells. Results: Insulin effects on placental gene expression underwent developmental changes from trophoblasts in the first trimester to endothelial cells at term that were paralleled by changes in levels of activated insulin receptors. The changes in gene regulation were both quantitative (i.e. magnitude of effect) and qualitative (i.e. specific genes affected and direction of regulation). Conclusions/interpretation: This spatio-temporal shift in insulin sensitivity throughout pregnancy allows maternal and foetal insulin to regulate different processes within the placenta at different gestational stages, facilitated by compartmentalisation of the insulin response. Thus, by altering the levels and function of insulin receptors in space and time, control of insulin-dependent processes in the human placenta will change from mother to foetus throughout gestation. This will be of particular interest in conditions associated with altered maternal or foetal insulin levels, i.e. diabetes mellitus or intrauterine growth restriction.

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Insulin-Regulated Gene Expression

Cited by 49 publications

References 0 publications

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

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

The FoxO transcription factors and metabolic regulation

Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy

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