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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145035/ https://www.ncbi.nlm.nih.gov/pubmed/33946318 http://dx.doi.org/10.3390/antiox10050711 |
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author | Wardelmann, Kristina Rath, Michaela Castro, José Pedro Blümel, Sabine Schell, Mareike Hauffe, Robert Schumacher, Fabian Flore, Tanina Ritter, Katrin Wernitz, Andreas Hosoi, Toru Ozawa, Koichiro Kleuser, Burkhard Weiß, Jürgen Schürmann, Annette Kleinridders, André |
author_facet | Wardelmann, Kristina Rath, Michaela Castro, José Pedro Blümel, Sabine Schell, Mareike Hauffe, Robert Schumacher, Fabian Flore, Tanina Ritter, Katrin Wernitz, Andreas Hosoi, Toru Ozawa, Koichiro Kleuser, Burkhard Weiß, Jürgen Schürmann, Annette Kleinridders, André |
author_sort | Wardelmann, Kristina |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-8145035 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81450352021-05-26 Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus Wardelmann, Kristina Rath, Michaela Castro, José Pedro Blümel, Sabine Schell, Mareike Hauffe, Robert Schumacher, Fabian Flore, Tanina Ritter, Katrin Wernitz, Andreas Hosoi, Toru Ozawa, Koichiro Kleuser, Burkhard Weiß, Jürgen Schürmann, Annette Kleinridders, André Antioxidants (Basel) Article 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. MDPI 2021-04-30 /pmc/articles/PMC8145035/ /pubmed/33946318 http://dx.doi.org/10.3390/antiox10050711 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wardelmann, Kristina Rath, Michaela Castro, José Pedro Blümel, Sabine Schell, Mareike Hauffe, Robert Schumacher, Fabian Flore, Tanina Ritter, Katrin Wernitz, Andreas Hosoi, Toru Ozawa, Koichiro Kleuser, Burkhard Weiß, Jürgen Schürmann, Annette Kleinridders, André Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145035/ https://www.ncbi.nlm.nih.gov/pubmed/33946318 http://dx.doi.org/10.3390/antiox10050711 |
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