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Foxo Transcription Factors Activate Akt and Attenuate Insulin Signaling in Heart by Inhibiting Protein Phosphatases

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Foxo Transcription Factors Activate Akt and Attenuate Insulin Signaling in Heart by Inhibiting Protein Phosphatases FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases Yan G. Ni*†, Na Wang*, Dian J. Cao*, Nita Sachan*, David J. Morris*, Robert D. Gerard*‡, Makoto Kuro-o§, Beverly A. Rothermel*, and Joseph A. Hill*‡¶ʈ ¶Donald W. Reynolds Cardiovascular Clinical Research Center, Departments of *Internal Medicine (Cardiology), ‡Molecular Biology, and §Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573 Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved November 7, 2007 (received for review November 21, 2006) Insulin resistance and metabolic syndrome are rapidly expanding The O subfamily of Forkhead/winged helix transcription factors public health problems. Acting through the PI3K/Akt pathway, (FoxO) plays important roles in regulating cardiac and skeletal insulin and insulin-like growth factor-1 (IGF-1) inactivate FoxO muscle remodeling (8–11). FoxO proteins are phylogenetically transcription factors, a class of highly conserved proteins impor- conserved and regulate key physiological functions, including cell tant in numerous physiological functions. However, even as FoxO proliferation, cell differentiation, and survival (12–15). In addition, is a downstream target of insulin, FoxO factors also control FoxO functions in complex ways to regulate insulin signaling and upstream signaling elements governing insulin sensitivity and glucose and lipid metabolism (13, 16). In Drosophila, activation of glucose metabolism. Here, we report that sustained activation of dFoxO in fat body represses insulin-dependent signaling and in- either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of creases life span (17). Similarly in mammals, FoxO1 regulates Akt phosphorylation and kinase activity. FoxO-activated Akt di- multiple metabolic pathways in liver and pancreatic ␤-cells (18), and rectly interacts with and phosphorylates FoxO, providing feedback transgenic expression of FoxO1 in various tissues leads to impaired inhibition. We reported previously that FoxO factors attenuate insulin sensitivity and glucose intolerance (18–20). On the other cardiomyocyte calcineurin (PP2B) activity. We now show that hand, both dFoxO and the mammalian equivalent FoxO1 activate calcineurin forms a complex with Akt and inhibition of calcineurin transcription of the insulin receptor and insulin receptor substrate-2 enhances Akt phosphorylation. In addition, FoxO activity sup- (IRS-2) in Drosophila S2 cells and mouse C2C12 cells, which presses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and sensitizes the cellular response to insulin (21). Also, whereas Akt–calcineurin interactions. Repression of Akt–PP2A/B interac- transgenic overexpression of constitutively active FoxO1 (caFoxO1) tions and phosphatase activities contributes, at least in part, to in liver triggers impaired fasting glucose and hyperinsulinemia (18, FoxO-dependent increases in Akt phosphorylation and kinase 22), acute overexpression of caFoxO1 in liver reduces plasma activity. Resveratrol, an activator of Sirt1, increases the transcrip- insulin, glucose, and triglycerides (23). And paradoxically, FoxO3- tional activity of FoxO1 and triggers Akt phosphorylation in heart. deficient mice exhibit impaired insulin sensitivity (24). Thus, many Importantly, FoxO-mediated increases in Akt activity diminish questions remain regarding the roles of FoxO proteins in insulin insulin signaling, as manifested by reduced Akt phosphorylation, signaling and their potential contribution to myocardial insulin reduced membrane translocation of Glut4, and decreased insulin- resistance. triggered glucose uptake. Also, inactivation of the gene coding for An additional layer of complexity exists in that the transcriptional FoxO3 enhances insulin-dependent Akt phosphorylation. Taken activity of FoxO is regulated by insulin through the phosphoinosi- together, this study demonstrates that changes in FoxO activity tide-3 kinase (PI3K)/Akt signaling pathway. Both insulin and have a dose-responsive repressive effect on insulin signaling in insulin-like growth factor-1 (IGF-1) induce PI3K/Akt-dependent cardiomyocytes through inhibition of protein phosphatases, which phosphorylation of FoxO, which facilitates its interaction with 14-3-3 protein, leading to nuclear exclusion and eventual ubiqui- leads to altered Akt activation, reduced insulin sensitivity, and tylation-dependent proteasomal degradation (25). Thus, it is well impaired glucose metabolism. established that Akt (also known as protein kinase B, or PKB) plays a key role in repressing FoxO transcriptional activity. cardiomyocyte ͉ calcineurin ͉ insulin resistance ͉ cardiomyopathy Immediately upstream of FoxO, the activity of Akt itself is governed by several protein kinases and phosphatases. Akt is ardiovascular disease is the primary cause of death in patients activated by phosphorylation at Thr-308 within its catalytic domain Cwith obesity and type 2 diabetes mellitus. Insulin resistance, a by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and by major mechanism underlying these disorders, also contributes to phosphorylation at Ser-473 within a C-terminal hydrophobic motif several cardiovascular disease-promoting factors, which, together, comprise the metabolic syndrome (1). In addition to its deleterious effects on metabolic parameters, such as lipid dyscrasias and blood Author contributions: Y.G.N., B.A.R., and J.A.H. designed research; Y.G.N., N.W., D.J.C., and pressure, insulin resistance of myocardial muscle itself has been D.J.M. performed research; N.S., R.D.G., and M.K.-o. contributed new reagents/analytic tools; Y.G.N. and J.A.H. analyzed data; and Y.G.N. and J.A.H. wrote the paper. documented in patients with type 2 diabetes and in nondiabetic The authors declare no conflict of interest. subjects with angiographically proven coronary artery disease (2). MEDICAL SCIENCES Indeed, strong evidence suggests that diabetes affects cardiac This article is a PNAS Direct Submission. structure and function, independent of blood pressure and coro- †Present address: Division of Cardiovascular Diseases, Merck Research Laboratories, Rah- way, NJ 07065. nary artery disease (3, 4). Insulin resistance has also been docu- ʈTo whom correspondence should be addressed at: Division of Cardiology, University of mented in heart tissue undergoing hypertrophic or atrophic remod- Texas Southwestern Medical Center, NB11.200, 6000 Harry Hines Boulevard, Dallas, TX eling (5, 6). Although much is known already regarding metabolic 75390-8573. E-mail: [email protected]. and insulin signaling pathways in the heart (3, 6, 7), there is This article contains supporting information online at www.pnas.org/cgi/content/full/ continued interest in defining mechanisms that govern insulin 0610290104/DC1. resistance and myocardial plasticity. © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0610290104 PNAS ͉ December 18, 2007 ͉ vol. 104 ͉ no. 51 ͉ 20517–20522 Downloaded by guest on October 1, 2021 1 P-Akt S473 that stem from supraphysiological levels of expression. To test this O 1 x P-Akt T308 A evitaleR BtkA/tkA-P O o P x F possibility, we evaluated a dose–response relation between FoxO F o a 4 F c ** G ** ** 3 expression and Akt activation. In these experiments, we observed P-Akt (T308) slevel ** 2 significant increases in Akt phosphorylation even in cells infected P-Akt (S473) 1 with FoxO1 adenovirus at very low titers [multiplicity of infection Akt ϭ Tubulin 0 (MOI) 1, Fig. 1D]. In vitro kinase assays revealed significant GFP FoxO1 caFoxO1 increases in Akt kinase activity in cardiomyocytes overexpressing FoxO1 or caFoxO1 (Fig. 1E). We observed no effects of FoxO 3 C O D x o GFP FoxO1 overexpression on the phosphorylation levels of p38, p42/44 (ERK) P F F a G c 10 3 1 10 3 1 Adenovirus (MOI) MAP kinases, or Jun-amino-terminal kinase (JNK) (Fig. 1F), P-Akt (T308) FoxO1-GFP suggesting specificity of the pathway. P-Akt (S473) FoxO3/1 Next, we tested whether endogenous FoxO was capable of P-Akt (S473) Akt activating Akt. To accomplish this, we treated cells with resveratrol (RVT), an activator of the type III histone deacetylase Sirt1. E F Deacetylation by Sirt1 stabilizes the FoxO1 protein by preventing esanik 1 3 O * 1 x O o its proteasomal degradation (14). In addition, resveratrol increases P x F F o a G F c ytivitca 2 FoxO1 nuclear translocation and consequent expression of FoxO1 tkA * P-p38 MAPK (T180/Y182) target genes in hepatocytes (31). We observed similar results in evitaleR 1 P-p42/44 MAPK (T202/Y204) cardiomyocytes, where resveratrol increased the nuclear (active) 0 P-SAPK/JNK (Thr183/Tyr185) fraction of FoxO1, an effect opposite to that of IGF-1 [supporting GFP FoxO1 caFoxO1 Tubulin information (SI) Fig. 6 A and B]. Resveratrol also increased nuclear FoxO1 in the presence of IGF-1 (SI Fig. 6 A and B), suggesting that Fig. 1. FoxO proteins increase basal levels of Akt phosphorylation and kinase FoxO1 deacetylation in cardiac myocytes can override phosphory- activity. Cardiomyocytes were infected with adenovirus encoding GFP, FoxO1- lation-dependent mechanisms. Further, quantitative real-time PCR GFP, caFoxO1-GFP, or caFoxO3-GFP, and whole cell lysates were harvested 24 h showed that resveratrol elicited a significant increase in the mRNA after infection. (A–C) Western blots (A and C) and densitometric analyses (B) abundance of atrogin-1, a target gene of FoxO1 and FoxO3 (SI Fig. of phospho-Akt
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