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Ortega-Molina A.,Tumor Suppression Group | Efeyan A.,Tumor Suppression Group | Lopez-Guadamillas E.,Tumor Suppression Group | Munoz-Martin M.,Tumor Suppression Group | And 12 more authors.
Cell Metabolism | Year: 2012

Aging in worms and flies is regulated by the PI3K/Akt/Foxo pathway. Here we extend this paradigm to mammals. Pten tg mice carrying additional genomic copies of Pten are protected from cancer and present a significant extension of life span that is independent of their lower cancer incidence. Interestingly, Pten tg mice have an increased energy expenditure and protection from metabolic pathologies. The brown adipose tissue (BAT) of Pten tg mice is hyperactive and presents high levels of the uncoupling protein Ucp1, which we show is a target of Foxo1. Importantly, a synthetic PI3K inhibitor also increases energy expenditure and hyperactivates the BAT in mice. These effects can be recapitulated in isolated brown adipocytes and, moreover, implants of Pten tg fibroblasts programmed with Prdm16 and Cebpβ form subcutaneous brown adipose pads more efficiently than wild-type fibroblasts. These observations uncover a role of Pten in promoting energy expenditure, thus decreasing nutrient storage and its associated damage. © 2012 Elsevier Inc.

Vidal J.,Hospital Clinic Universitari | Vidal J.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | Vidal J.,Institute dInvestigacions Biomediques August Pi Sunyer IDIBAPS | Jimenez A.,Hospital Clinic Universitari
Current Atherosclerosis Reports | Year: 2013

The parallel occurrence of improved glucose tolerance and increased glucagon-like peptide 1 (GLP-1) response to meal intake following metabolic surgery (MS) demonstrated in several studies has led to the notion that GLP-1 is the culprit for the impressive rates of remission of type 2 diabetes mellitus (T2DM) following MS. In this article, we critically review current evidence supporting this view. Recent studies specifically designed to elucidate a causative role of GLP-1 in the antidiabetic effects of MS call into question GLP-1 as a key player for T2DM outcome following MS procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy in morbidly obese subjects. Whether GLP-1 plays a more prominent role in the remission of T2DM following MS in subjects with moderate obesity warrants further studies. Appraisal of the mechanisms involved in the amelioration of hyperglycemia following MS is a priority, as it could help in the battle against the current combined epidemics of obesity and T2DM. © 2013 Springer Science+Business Media New York.

Cordero-Herrera I.,Institute of Food Science and Technology and Nutrition ICTAN | Martin M.A.,Institute of Food Science and Technology and Nutrition ICTAN | Martin M.A.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | Bravo L.,Institute of Food Science and Technology and Nutrition ICTAN | And 2 more authors.
Molecular Nutrition and Food Research | Year: 2013

Scope: Cocoa and (-)-epicatechin (EC), a main cocoa flavanol, have been suggested to exert beneficial effects in diabetes, but the mechanism for their insulin-like effects remains unknown. In this study, the modulation of insulin signalling by EC and a cocoa phenolic extract (CPE) on hepatic HepG2 cells was investigated by analysing key proteins of the insulin pathways, namely insulin receptor, insulin receptor substrate (IRS) 1 and 2, PI3K/AKT and 5′-AMP-activated protein kinase (AMPK), as well as the levels of the glucose transporter GLUT-2 and the hepatic glucose production. Methods and results: EC and CPE enhanced the tyrosine phosphorylation and total insulin receptor, IRS-1 and IRS-2 levels and activated the PI3K/AKT pathway and AMPK in HepG2 cells. CPE also enhanced the levels of GLUT-2. Interestingly, EC and CPE modulated the expression of phosphoenolpyruvate carboxykinase, a key protein involved in the gluconeogenesis, leading to a diminished glucose production. In addition, EC- and CPE-regulated hepatic gluconeogenesis was prevented by the blockage of AKT and AMPK. Conclusion: Our data suggest that EC and CPE strengthen the insulin signalling by activating key proteins of that pathway and regulating glucose production through AKT and AMPK modulation in HepG2 cells. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Griffeth R.J.,Research Center Principe Felipe | Carretero J.,University of Salamanca | Burks D.J.,Research Center Principe Felipe | Burks D.J.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas
PLoS ONE | Year: 2013

Insulin receptor substrate (IRS) proteins are key mediators of insulin and insulin-like growth factor (IGF) signalling. In mice, deletion of Irs1 is associated with profound growth retardation and increased longevity whereas Irs2-deficiency causes diabetes and female infertility. Clinical studies suggest that diabetes and obesity diminish male fertility. However, the role of IRS proteins in male reproduction is unknown. We observed that testis weight is reduced by 45% in Irs2-deficient mice as compared with control males. The weight of these organs in Irs1-/- males was similar to controls; however, since Irs1-deficient mice are 50% smaller, testis weight:body weight was increased in this model. Neonatal Irs2-/- mice also exhibited reduced testicular size, suggesting that impairments in this model occur during development. Histological examination of testicular cross sections from Irs2-/- mice revealed normal cellular associations without obvious abnormalities in the seminiferous epithelium. Reduced testicular weight was associated with fewer Sertoli cells, spermatogonia, spermatocytes, elongated spermatids, and epididymal spermatozoa. However, Leydig cell number and the concentration of serum testosterone were equivalent between Irs2-deficient and control males. Testicular weight was reduced similarly in non-diabetic and diabetic Irs2-/- mice, indicating that hyperglycemia does not compound the effects of Irs2 deletion on impaired testis development. Expression of Irs1, Irs3, and Irs4 was comparable between experimental groups. Collectively, our results demonstrate that IRS2 plays a critical role in testicular development, potentially by mediating IGF1 signalling during embryonic and early postnatal development. © 2013 Griffeth et al.

Duran J.,Barcelona Institute for Research in Biomedicine | Duran J.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | Guinovart J.J.,Barcelona Institute for Research in Biomedicine | Guinovart J.J.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | Guinovart J.J.,University of Barcelona
Molecular Aspects of Medicine | Year: 2015

Glycogen is present in the brain at much lower concentrations than in muscle or liver. However, by characterizing an animal depleted of brain glycogen, we have shown that the polysaccharide plays a key role in learning capacity and in activity-dependent changes in hippocampal synapse strength. Since glycogen is essentially found in astrocytes, the diverse roles proposed for this polysaccharide in the brain have been attributed exclusively to these cells. However, we have demonstrated that neurons have an active glycogen metabolism that contributes to tolerance to hypoxia. However, these cells can store only minute amounts of glycogen, since the progressive accumulation of this molecule leads to neuronal loss. Loss-of-function mutations in laforin and malin cause Lafora disease. This condition is characterized by the presence of high numbers of insoluble polyglucosan bodies, known as Lafora bodies, in neuronal cells. Our findings reveal that the accumulation of this aberrant glycogen accounts for the neurodegeneration and functional consequences, as well as the impaired autophagy, observed in models of this disease. Similarly glycogen synthase is responsible for the accumulation of corpora amylacea, which are polysaccharide-based aggregates present in the neurons of aged human brains. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism is important under stress conditions and that neuronal glycogen accumulation contributes to neurodegenerative diseases and to aging-related corpora amylacea formation. © 2015 Elsevier Ltd.

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