Transcriptional feedback control of insulin receptor by dFOXO/FOXO1

Abstract

The insulin signaling pathway, which is conserved in evolution from flies to humans, evolved to allow a fast response to changes in nutrient availability while keeping glucose concentration constant in serum. Here we show that, both in Drosophila and mammals, insulin receptor (InR) represses its own synthesis by a feedback mechanism directed by the transcription factor dFOXO/FOXO1. In Drosophila, dFOXO is responsible for activating transcription of dInR, and nutritional conditions can modulate this effect. Starvation up-regulates mRNA of dInR in wild-type but not dFOXO-deficient flies. Importantly, FOXO1 acts in mammalian cells like its Drosophila counterpart, up-regulating the InR mRNA level upon fasting. Mammalian cells up-regulate the InR mRNA in the absence of serum, conditions that induce the dephosphorylation and activation of FOXO1. Interestingly, insulin is able to reverse this effect. Therefore, dFOXO/FOXO1 acts as an insulin sensor to activate insulin signaling, allowing a fast response to the hormone after each meal. Our results reveal a key feedback control mechanism for dFOXO/FOXO1 in regulating metabolism and insulin signaling.

B Cell Receptor Signaling Down-Regulates Forkhead Box Transcription Factor Class O 1 mRNA Expression via Phosphatidylinositol 3-Kinase and Bruton’s Tyrosine Kinase

“…1C). Culture in medium alone also resulted in some decrease in FOXO1 protein levels (data not shown), most likely due to the ability of growth factors present in serum to induce the phosphorylation and degradation of FOXO1 protein (34). However, the down-regulation of FOXO1 mRNA was specific for the BCR-induced signals and was not observed in the presence of medium alone (Fig.…”

Forkhead transcription factors regulate mosquito reproduction

“…dFoxO regulates insulin signaling in the brain and fat body, along with controlling fertility and lifespan (Hwangbo et al, 2004a). FoxO manifests this effect through exhibiting transcriptional feedback control of the insulin receptor (Puig & Tjian, 2005). Together, these studies stress the importance of Fox transcription factors for regulating development and homeostasis in Drosophila.…”

Insulin signaling and limb-patterning: candidate pathways for the origin and evolutionary diversification of beetle ‘horns’

“…However, during the period of maximal horn growth (late Period II) there is a highly significant (Po0.0001) difference in expression of the InR gene that is associated with horn growth: horn cells from small males and females had significantly higher levels of InR transcript than similar cells from large males. (b) The insulin signaling pathway, illustrating one explanation for this result: as signaling through the insulin pathway is increased overall in large males, the expression of InR decreases in horn discs due to kinase-dependent inactivation of its transcriptional activator FOXO by PKB/Akt (red bar; Kramer et al, 2003;Puig and Tijan, 2005). (c) In horn discs of small males and females pathway activity is truncated at some point downstream from the insulin receptor (tissue 'reprogramming' resulting from the mechanism of horn dimorphism).…”

“…(c) In horn discs of small males and females pathway activity is truncated at some point downstream from the insulin receptor (tissue 'reprogramming' resulting from the mechanism of horn dimorphism). Reduced signaling through this pathway keeps FOXO in an activated state, causing an upregulation of InR transcription (Puig and Tijan, 2005) and shutting off cell proliferation through the transcriptional inhibitor 4E-BP (red arrows; Junger et al, 2003). Data from D Emlen, L Corley, I Dworkin and Q Szafran, in preparation.…”

“…Beetle horn development and evolution DJ Emlen et al Tijan, 2005). However, large females, and probably even small males are not starved, and in these animals the arrested development applies to only a single structure, the horns, at a time when other traits like wings and eyes are still growing.…”