Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus
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 reduc...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-04-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/5/711 |
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| author | Kristina Wardelmann 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 André Kleinridders |
| author_facet | Kristina Wardelmann 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 André Kleinridders |
| author_sort | Kristina Wardelmann |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T11:48:21Z |
| format | Article |
| id | doaj.art-9db7b1040f554f3f80b1b7f6dd84a90e |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T11:48:21Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-9db7b1040f554f3f80b1b7f6dd84a90e2023-11-21T17:56:10ZengMDPI AGAntioxidants2076-39212021-04-0110571110.3390/antiox10050711Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the HypothalamusKristina Wardelmann0Michaela Rath1José Pedro Castro2Sabine Blümel3Mareike Schell4Robert Hauffe5Fabian Schumacher6Tanina Flore7Katrin Ritter8Andreas Wernitz9Toru Hosoi10Koichiro Ozawa11Burkhard Kleuser12Jürgen Weiß13Annette Schürmann14André Kleinridders15Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, GermanyJunior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, GermanyDepartment of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, GermanyJunior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, GermanyJunior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, GermanyJunior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, GermanyInstitute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, GermanyJunior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, GermanyJunior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, GermanyDepartment of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, GermanyDepartment of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigaku-dori, Sanyo Onoda, Yamaguchi 756-0884, JapanDepartment of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanInstitute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, GermanyGerman Center for Diabetes Research (DZD), Ingolstaedter Land Str. 1, 85764 Neuherberg, GermanyGerman Center for Diabetes Research (DZD), Ingolstaedter Land Str. 1, 85764 Neuherberg, GermanyJunior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, GermanyMitochondria 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.https://www.mdpi.com/2076-3921/10/5/711brain insulin signalingmitochondriaoxidative stressfatty acid metabolism |
| spellingShingle | Kristina Wardelmann 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 André Kleinridders Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus Antioxidants brain insulin signaling mitochondria oxidative stress fatty acid metabolism |
| title | Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus |
| title_full | Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus |
| title_fullStr | Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus |
| title_full_unstemmed | Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus |
| title_short | Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus |
| title_sort | central acting hsp10 regulates mitochondrial function fatty acid metabolism and insulin sensitivity in the hypothalamus |
| topic | brain insulin signaling mitochondria oxidative stress fatty acid metabolism |
| url | https://www.mdpi.com/2076-3921/10/5/711 |
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