Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2

Bacquer, Olivier Le; Petroulakis, Emmanuel; Paglialunga, Sabina; Poulin, Francis; Richard, Denis; Cianflone, Katherine; Sonenberg, Nahum

doi:10.1172/jci29528

Cited by 296 publications

(303 citation statements)

References 60 publications

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“…1). Moreover, 4EBP knockout mice have been generated and characterised but no effects on b-cell mass or glucose homoeostasis have been reported (TsukiyamaKohara et al 2001, Le Bacquer et al 2007. Interestingly, we show that inhibition of another target of mTORC1, S6K1, inhibits islet cell proliferation.…”

Section: Discussionmentioning

confidence: 53%

Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/S6K1

Xie¹,

El-Sayed²,

Cheng³

et al. 2014

Journal of Molecular Endocrinology

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Glucagon-like peptide 1 receptor (GLP1R) agonists, such as exendin-4, potentiate glucosestimulated insulin secretion and are currently used in the management of type 2 diabetes. Interestingly, GLP1R agonists also have the ability to augment b-cell mass. In this report, we provide evidence that in the presence of glucose, exendin-4 stimulates rodent islet cell DNA replication via the activation of ribosomal protein S6 kinase 1 (S6K1) and that this is mediated by the protein kinase B (PKB)-dependent activation of mTOR complex 1 (mTORC1). We show that activation of this pathway is caused by the autocrine or paracrine activation of the IGF1 receptor (IGF1R), as siRNA-mediated knockdown of the IGF1R effectively blocked exendin-4-stimulated PKB and mTORC1 activation. In contrast, pharmacological inactivation of the epidermal growth factor receptor has no discernible effect on exendin-4-stimulated PKB or mTORC1 activation. Therefore, we conclude that GLP1R agonists stimulate b-cell proliferation via the PKB-dependent stimulation of mTORC1/S6K1 whose activation is mediated through the autocrine/paracrine activation of the IGF1R. This work provides a better understanding of the molecular basis of GLP1 agonist-induced b-cell proliferation which could potentially be exploited in the identification of novel drug targets that increase b-cell mass.

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Section: Discussionmentioning

confidence: 53%

Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/S6K1

Xie¹,

El-Sayed²,

Cheng³

et al. 2014

Journal of Molecular Endocrinology

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“…[1][2][3][4] Until recently, most of the evidence supporting the role of mTORC1 in insulin-sensitive tissues was derived from the use of rapamycin and alterations in insulin sensitivity in global S6K and 4E-bp-deficient mice. 1,9,51 However, abnormalities in multiple tissues observed in global knockouts and catalytic unit of two distinct complexes, mTORC1 and 2, 12,13 which both contain mTOR, mLST8 (mammalian lethal with SEC13 protein)/GβL (G-protein β-protein subunit-like) and Deptor (DEP domain-containing mTOR-interacting protein) (Fig. 1).…”

Section: Tsc/mtor Plays a Critical Rolementioning

confidence: 99%

“…Unfortunately, the specific β-cell phenotype of these animals was not analyzed. 51 Recent studies have also revealed an important role for 4E-BP in protection against endoplasmic reticulum (ER) stress in β cells. Expression of 4e-bp1 was increased by direct transcriptional activation of the Eif4e-bp1 gene in islets under ER stress in several mouse models of diabetes.…”

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confidence: 99%

mTORC1 signaling and regulation of pancreatic β-cell mass

et al. 2012

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T he capacity of β cells to expand in response to insulin resistance is a critical factor in the development of type 2 diabetes. Proliferation of β cells is a major component for these adaptive responses in animal models. The extracellular signals responsible for β-cell expansion include growth factors, such as insulin, and nutrients, such as glucose and amino acids. AKT activation is one of the important components linking growth signals to the regulation of β-cell expansion. Downstream of AKT, tuberous sclerosis complex 1 and 2 (TSC1/2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling have emerged as prime candidates in this process, because they integrate signals from growth factors and nutrients. Recent studies demonstrate the importance of mTORC1 signaling in β cells. This review will discuss recent advances in the understanding of how this pathway regulates β-cell mass and present data on the role of TSC1 in modulation of β-cell mass. Herein, we also demonstrate that deletion of Tsc1 in pancreatic β cells results in improved glucose tolerance, hyperinsulinemia and expansion of β-cell mass that persists with aging.

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“…Global inactivation of S6K1 in knock-out mice protects the mice against diet-induced insulin resistance (21). An increase in S6K1 activity leads to insulin resistance in mice (22). In humans, inhibition of the S6K activity by rapamycin leads to protection against insulin resistance (23).…”

mentioning

confidence: 99%

Inactivation of NF-κB p50 Leads to Insulin Sensitization in Liver through Post-translational Inhibition of p70S6K

Gao

Yin

Zhang

et al. 2009

Journal of Biological Chemistry

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In this study, we investigated the metabolic phenotype of the NF-B p50 knock-out (p50-KO) mice. Compared with wild type mice, the p50-KO mice had an increase in food intake, but a decrease in body fat content. On chow diet, their blood glucose dropped much more than the wild type (WT) mice in the insulin tolerance test. Their glucose infusion rate was 30% higher than that of the WT mice in the hyperinsulinemic-euglycemic clamp. Their hepatic glucose production was suppressed more actively by insulin, and their insulin-induced glucose uptake was not altered in skeletal muscle or adipose tissue. In the liver, their p70S6K (S6K1) protein was significantly lower, and tumor necrosis factor-␣ (TNF-␣) expression was much higher. Their S6K1 protein was reduced by TNF-␣ treatment in the primary culture of hepatocytes. S6K1 reduction was blocked by the proteasome inhibitor MG132. In their livers, IKK2 (IKK␤) activity was reduced together with IKK␥. Their S6K1 degradation was dependent on IKK2 deficiency. Reconstitution of the S6K1 protein in their liver blocked the increase in insulin sensitivity. S6K1 degradation was not observed in hepatocytes of the WT mice. The data suggest that inactivation of NF-B p50 leads to suppression of IKK2 activity in the liver. IKK2 deficiency leads to S6K1 inhibition through TNF-induced protein degradation. The S6K1 reduction may contribute to insulin sensitivity in p50-KO mice. This study suggests that hepatic S6K1 may be a drug target in the treatment of insulin resistance.Chronic inflammation occurs in adipose tissue and liver in obesity (1, 2). It is generally believed that inflammation contributes to pathogenesis of insulin resistance through activation of IKK/NF-B and JNK signaling pathways. Serine kinase IKK2 (IKK␤) contributes to insulin resistance by activation of transcription factor NF-B (3-6) or induction of IRS-1 serine phosphorylation (7,8). Data from Ikk2 transgenic mice suggest that NF-B may be involved in the pathogenesis of insulin resistance (4). However, the role of NF-B has not been directly tested by gene knock-out in mice.NF-B contains two subunits, p50 (NF-B1) and p65 (RelA), in most cases. The p50 knock-out (p50-KO) mice were first reported in 1995, in which the p50 gene was globally inactivated by gene deletion (9). The mice are normal in growth, but deficient in B lymphocyte function. The p50-KO mice have been used in the study of many biological systems including the immune system (10, 11), muscle dystrophy (12), liver regeneration (13, 14), aging (15), and brain function (16). However, the metabolic phenotype remains unclear in this line of KO mice. Whole body knock-out of p65 (p65-KO) was reported in 1995 for embryonic lethality (17, 18). S6K1 (p70 ribosomal protein S6 kinase) is a serine kinase in the PI3K/Akt signaling pathway. It mediates nutrient (amino acid and glucose) and insulin signals in the regulation of insulin sensitivity (19,20). Global inactivation of S6K1 in knock-out mice protects the mice against diet-induced insulin resistance (21). An increa...

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Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2

Cited by 296 publications

References 60 publications

Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/S6K1

Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/S6K1

mTORC1 signaling and regulation of pancreatic β-cell mass

Inactivation of NF-κB p50 Leads to Insulin Sensitization in Liver through Post-translational Inhibition of p70S6K

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