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PAS Kinase as a Nutrient Sensor in Neuroblastoma and Hypothalamic Cells Required for the Normal Expression and Activity of Other Cellular Nutrient and Energy Sensors

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Abstract

PAS kinase (PASK) is a nutrient sensor that is highly conserved throughout evolution. PASK-deficient mice reveal a metabolic phenotype similar to that described in S6 kinase-1 S6K1-deficient mice that are protected against obesity. Hypothalamic metabolic sensors, such as AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR), play an important role in feeding behavior, the homeostasis of body weight, and energy balance. These sensors respond to changes in nutrient levels in the hypothalamic areas involved in feeding behavior and in neuroblastoma N2A cells, and we have recently reported that those effects are modulated by the anorexigenic peptide glucagon-like peptide-1 (GLP-1). Here, we identified PASK in both N2A cells and rat VMH and LH areas and found that its expression is regulated by glucose and GLP-1. High levels of glucose decreased Pask gene expression. Furthermore, PASK-silenced N2A cells record an impaired response by the AMPK and mTOR/S6K1 pathways to changes in glucose levels. Likewise, GLP-1 effect on the activity of AMPK, S6K1, and other intermediaries of both pathways and the regulatory role at the level of gene expression were also blocked in PASK-silenced cells. The absence of response to low glucose concentrations in PASK-silenced cells correlates with increased ATP content, low expression of mRNA coding for AMPK upstream kinase LKB1, and enhanced activation of S6K1. Our findings indicate that, at least in N2A cells, PASK is a key kinase in GLP-1 actions and exerts a coordinated response with the other metabolic sensors, suggesting that PASK might play an important role in feeding behavior.

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Acknowledgments

This work was supported by grants from MICINN (SAF2006-0475 and SAF2009-11297), Ayudas del Programa de Creación y Consolidación de Grupos de Investigación UCM-Banco Santander (GR58/08, GR35/10A, GR35/10B and GR42/10), Fundación de Investigación Médica Mutua Madrileña and IODURE project, CIBER de Diabetes y Enfermedades Metabólicas Asociadas, an initiative of ISCIII (Ministerio de Ciencia e Innovación).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, sn, 28040, Madrid, Spain

    Verónica Hurtado-Carneiro, Isabel Roncero, Enrique Blazquez, Elvira Alvarez & Carmen Sanz

  2. The Center for Biomedical Research in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain

    Verónica Hurtado-Carneiro, Isabel Roncero, Enrique Blazquez, Elvira Alvarez & Carmen Sanz

  3. Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain

    Carmen Sanz

  4. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Plaza S. Ramón y Cajal, s/n, 28040, Madrid, Spain

    Elvira Alvarez

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  1. Verónica Hurtado-Carneiro
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Correspondence to Elvira Alvarez.

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Elvira Alvarez and Carmen Sanz contributed equally to this work.

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Hurtado-Carneiro, V., Roncero, I., Blazquez, E. et al. PAS Kinase as a Nutrient Sensor in Neuroblastoma and Hypothalamic Cells Required for the Normal Expression and Activity of Other Cellular Nutrient and Energy Sensors. Mol Neurobiol 48, 904–920 (2013). https://doi.org/10.1007/s12035-013-8476-9

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