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Fernandez-Veledo S.,Rovira i Virgili University | Fernandez-Veledo S.,CIBER ISCIII | Vazquez-Carballo A.,Complutense University of Madrid | Vila-Bedmar R.,Institute Investigacion Sanitaria La Princesa | And 4 more authors.
IUBMB Life | Year: 2013

Recent advances have demonstrated that the adipose tissue plays a central role in regulating overall energy balance. Obesity results from a chronic deregulation of energy balance, with energy intake exceeding energy expenditure. Recently, new mechanisms that control the obesity phenotype such as the equilibrium between white and brown adipose tissue function has been identified. In this context, it is becoming increasingly clear that in addition to cellular growth, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) also regulate lipid metabolism and adipogenesis. Here, we review recent advances in the understanding of the molecular mechanisms involved in white and brown differentiation programs focusing on AMPK and mTOR signaling pathways, which may play differential roles in white adipose tissue and brown adipose tissue development. In view of the worldwide epidemic of obesity and its associated metabolic disorders such as insulin resistance and type 2 diabetes, targeting these kinases may represent a potential approach for reducing adiposity and improving obesity-related diseases. Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc. Source

Casafont I.,University of Cantabria | Palanca A.,University of Cantabria | Lafarga V.,Autonomous University of Madrid | Lafarga V.,Institute Investigacion Sanitaria La Princesa | And 2 more authors.
Acta Neuropathologica | Year: 2011

Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat sensory ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0-G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons. © 2011 Springer-Verlag. Source

Vila-Bedmar R.,Institute Investigacion Sanitaria La Princesa | Cruces-Sande M.,Institute Investigacion Sanitaria La Princesa | Lucas E.,Institute Investigacion Sanitaria La Princesa | Willemen H.L.D.M.,University Utrecht | And 6 more authors.
Science Signaling | Year: 2015

Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide - binding protein) - coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high-fat diet - dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fasting glycemia, improved glucose tolerance, and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole-body glucose homeostasis. Moreover, when continued to be fed a high-fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of proinflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity. Copyright 2015 by the American Association for the Advancement of Science. Source

Vila-Bedmar R.,Institute Investigacion Sanitaria La Princesa | Murga C.,Institute Investigacion Sanitaria La Princesa | VanHook A.M.,Web Editor
Science Signaling | Year: 2015

This Podcast features an interview with Cristina Murga and Rocio Vila-Bedmar, authors of a Research Article that appears in the 21 July 2015 issue of Science Signaling, about how deleting the kinase GRK2 can counteract some of the metabolic effects of a bad diet. Obesity affects many of the body's normal functions, most notably metabolism. Obesity is associated with insulin resistance and reduced glucose tolerance, which can lead to type 2 diabetes. It also promotes hepatic steatosis, the accumulation of fat in the liver. Vila-Bedmar et al. show that deleting GRK2 can prevent further weight gain and hepatic steatosis and improve glucose sensitivity in obese mice. Deleting GRK2 improved these metabolic consequences of high-fat diet-induced obesity even if the kinase was deleted after the mice had already become obese and resistant to insulin. © 2015 American Association for the Advancement of Science. All rights Reserved. Source

Rocha-Perugini V.,Institute Investigacion Sanitaria La Princesa | Sanchez-Madrid F.,Institute Investigacion Sanitaria La Princesa
Frontiers in Immunology | Year: 2016

Tetraspanin-enriched microdomains (TEMs) are specialized membrane platforms driven by protein-protein interactions that integrate membrane receptors and adhesion molecules. Tetraspanins participate in antigen recognition and presentation by antigen-presenting cells (APCs) through the organization of pattern-recognition receptors (PRRs) and their downstream-induced signaling, as well as the regulation of MHC-II-peptide trafficking. T lymphocyte activation is triggered upon specific recognition of antigens present on the APC surface during immunological synapse (IS) formation. This dynamic process is characterized by a defined spatial organization involving the compartmentalization of receptors and adhesion molecules in specialized membrane domains that are connected to the underlying cytoskeleton and signaling molecules. Tetraspanins contribute to the spatial organization and maturation of the IS by controlling receptor clustering and local accumulation of adhesion receptors and integrins, their downstream signaling, and linkage to the actin cytoskeleton. This review offers a perspective on the important role of TEMs in the regulation of antigen recognition and presentation and in the dynamics of IS architectural organization. © 2016 Rocha-Perugini, Sánchez-Madrid and Martínez del Hoyo. Source

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