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Article

Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus

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Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
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German Center for Diabetes Research (DZD), Ingolstaedter Land Str. 1, 85764 Neuherberg, Germany
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Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
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Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany
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Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
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Aging and Aneuploidy Laboratory, IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal
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Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
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Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany
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Department of Toxicology, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
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Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany
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Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigaku-dori, Sanyo Onoda, Yamaguchi 756-0884, Japan
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Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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German Diabetes Center (DDZ), Leibniz Center for Diabetes Research, Institute for Clinical Biochemistry and Pathobiochemistry, 40225 Duesseldorf, Germany
*
Author to whom correspondence should be addressed.
Academic Editors: Vanessa Routh and Xavier Fioramonti
Antioxidants 2021, 10(5), 711; https://doi.org/10.3390/antiox10050711
Received: 24 March 2021 / Revised: 23 April 2021 / Accepted: 28 April 2021 / Published: 30 April 2021
(This article belongs to the Special Issue Antioxidants in Diabetes)
Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance. View Full-Text
Keywords: brain insulin signaling; mitochondria; oxidative stress; fatty acid metabolism brain insulin signaling; mitochondria; oxidative stress; fatty acid metabolism
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MDPI and ACS Style

Wardelmann, K.; Rath, M.; Castro, J.P.; Blümel, S.; Schell, M.; Hauffe, R.; Schumacher, F.; Flore, T.; Ritter, K.; Wernitz, A.; Hosoi, T.; Ozawa, K.; Kleuser, B.; Weiß, J.; Schürmann, A.; Kleinridders, A. Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus. Antioxidants 2021, 10, 711. https://doi.org/10.3390/antiox10050711

AMA Style

Wardelmann K, Rath M, Castro JP, Blümel S, Schell M, Hauffe R, Schumacher F, Flore T, Ritter K, Wernitz A, Hosoi T, Ozawa K, Kleuser B, Weiß J, Schürmann A, Kleinridders A. Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus. Antioxidants. 2021; 10(5):711. https://doi.org/10.3390/antiox10050711

Chicago/Turabian Style

Wardelmann, Kristina, Michaela Rath, José Pedro Castro, Sabine Blümel, Mareike Schell, Robert Hauffe, Fabian Schumacher, Tanina Flore, Katrin Ritter, Andreas Wernitz, Toru Hosoi, Koichiro Ozawa, Burkhard Kleuser, Jürgen Weiß, Annette Schürmann, and André Kleinridders. 2021. "Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus" Antioxidants 10, no. 5: 711. https://doi.org/10.3390/antiox10050711

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