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PAS Kinase Is a Nutrient and Energy Sensor in Hypothalamic Areas Required for the Normal Function of AMPK and mTOR/S6K1

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Abstract

The complications caused by overweight, obesity and type 2 diabetes are one of the main problems that increase morbidity and mortality in developed countries. Hypothalamic metabolic sensors play an important role in the control of feeding and energy homeostasis. PAS kinase (PASK) is a nutrient sensor proposed as a regulator of glucose metabolism and cellular energy. The role of PASK might be similar to other known metabolic sensors, such as AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). PASK-deficient mice resist diet-induced obesity. We have recently reported that AMPK and mTOR/S6K1 pathways are regulated in the ventromedial and lateral hypothalamus in response to nutritional states, being modulated by anorexigenic glucagon-like peptide-1 (GLP-1)/exendin-4 in lean and obese rats. We identified PASK in hypothalamic areas, and its expression was regulated under fasting/re-feeding conditions and modulated by exendin-4. Furthermore, PASK-deficient mice have an impaired activation response of AMPK and mTOR/S6K1 pathways. Thus, hypothalamic AMPK and S6K1 were highly activated under fasted/re-fed conditions. Additionally, in this study, we have observed that the exendin-4 regulatory effect in the activity of metabolic sensors was lost in PASK-deficient mice, and the anorexigenic properties of exendin-4 were significantly reduced, suggesting that PASK could be a mediator in the GLP-1 signalling pathway. Our data indicated that the PASK function could be critical for preserving the nutrient effect on AMPK and mTOR/S6K1 pathways and maintain the regulatory role of exendin-4 in food intake. Some of the antidiabetogenic effects of exendin-4 might be modulated through these processes.

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Acknowledgments

This work was supported by grants from Spain’s Ministry of Science and Innovation—MICINN (SAF2006-0475 and SAF2009-11297), the Complutense University-Banco Santander Funding Programme for the Creation and Consolidation of Research Teams (GR58/08, GR35/10A, GR35/10B and GR42/10), Mutua Madrileña Medical Research Foundation and the IODURE project, and the CIBER for Diabetes and Associated Metabolic Disorders (CIBERDEM) of the Carlos III Health Institute (ISCIII) (Ministry of Science and Innovation). We wish to thank Marketa Zemanova for her excellent technical assistance.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Plaza S. Ramón y Cajal, s/n, Madrid, 28040, Spain

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

  2. Institute of Physiology and Zurich Center for Integrative Human Physiology ZIHP, Zurich, Switzerland

    Sascha S. Egger & Roland H. Wenger

  3. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain

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

  4. Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Madrid, Spain

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

  5. Department of Cell Biology, Faculty of Medicine, Complutense University, Plaza S. Ramón y Cajal, s/n, Madrid, 28040, Spain

    Carmen Sanz

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  1. Verónica Hurtado-Carneiro
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  3. Sascha S. Egger
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Correspondence to Carmen Sanz.

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Carmen Sanz and Elvira Alvarez contributed equally to this work.

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Effects of PASK deficiency on the expression of several genes in the VMH and LH. Quantitative real-time PCR was used to analyze the expression of several genes as shown (Online resource 1). The mRNA levels were quantified in VMH and LH from fasted C57Bl/6 wild-type and PASK knockout mice in the presence or absence of exendin-4. The bars represent the ratios respect to β-actin of the mRNA levels of the different genes. The value obtained in VMH from wild-type mice (WT) treated with a vehicle without exendin-4 was taken as 1. Results are means ± SEM; n=3-4 animals per condition. *P<0.05, **P<0.01 WT vs. Pask; #P<0.05 vehicle vs. exendin-4; †P<0.05, ††P<0.01 VMH vs. LH. (GIF 39 kb)

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Hurtado-Carneiro, V., Roncero, I., Egger, S.S. et al. PAS Kinase Is a Nutrient and Energy Sensor in Hypothalamic Areas Required for the Normal Function of AMPK and mTOR/S6K1. Mol Neurobiol 50, 314–326 (2014). https://doi.org/10.1007/s12035-013-8630-4

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