PMID- 33946318 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210527 IS - 2076-3921 (Print) IS - 2076-3921 (Electronic) IS - 2076-3921 (Linking) VI - 10 IP - 5 DP - 2021 Apr 30 TI - Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus. LID - 10.3390/antiox10050711 [doi] LID - 711 AB - 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. FAU - Wardelmann, Kristina AU - Wardelmann K AD - Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. AD - German Center for Diabetes Research (DZD), Ingolstaedter Land Str. 1, 85764 Neuherberg, Germany. AD - Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. AD - Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany. FAU - Rath, Michaela AU - Rath M AUID- ORCID: 0000-0002-5766-0697 AD - Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. AD - Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany. FAU - Castro, Jose Pedro AU - Castro JP AD - Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. AD - Aging and Aneuploidy Laboratory, IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal. AD - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto, 4200-135 Porto, Portugal. FAU - Blumel, Sabine AU - Blumel S AD - Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. FAU - Schell, Mareike AU - Schell M AD - Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. AD - German Center for Diabetes Research (DZD), Ingolstaedter Land Str. 1, 85764 Neuherberg, Germany. AD - Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. FAU - Hauffe, Robert AU - Hauffe R AUID- ORCID: 0000-0003-3403-6573 AD - Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. AD - Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany. FAU - Schumacher, Fabian AU - Schumacher F AUID- ORCID: 0000-0001-8703-3275 AD - Institute of Pharmacy, Freie Universitat Berlin, Konigin-Luise-Str. 2+4, 14195 Berlin, Germany. AD - Department of Toxicology, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. FAU - Flore, Tanina AU - Flore T AD - Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. AD - Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. FAU - Ritter, Katrin AU - Ritter K AD - Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. FAU - Wernitz, Andreas AU - Wernitz A AD - Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. FAU - Hosoi, Toru AU - Hosoi T AD - Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigaku-dori, Sanyo Onoda, Yamaguchi 756-0884, Japan. FAU - Ozawa, Koichiro AU - Ozawa K AD - Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. FAU - Kleuser, Burkhard AU - Kleuser B AUID- ORCID: 0000-0002-1888-9595 AD - Institute of Pharmacy, Freie Universitat Berlin, Konigin-Luise-Str. 2+4, 14195 Berlin, Germany. AD - Department of Toxicology, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. FAU - Weiss, Jurgen AU - Weiss J AD - German Center for Diabetes Research (DZD), Ingolstaedter Land Str. 1, 85764 Neuherberg, Germany. AD - German Diabetes Center (DDZ), Leibniz Center for Diabetes Research, Institute for Clinical Biochemistry and Pathobiochemistry, 40225 Duesseldorf, Germany. FAU - Schurmann, Annette AU - Schurmann A AUID- ORCID: 0000-0002-4113-4377 AD - German Center for Diabetes Research (DZD), Ingolstaedter Land Str. 1, 85764 Neuherberg, Germany. AD - Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. FAU - Kleinridders, Andre AU - Kleinridders A AD - Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. AD - German Center for Diabetes Research (DZD), Ingolstaedter Land Str. 1, 85764 Neuherberg, Germany. AD - Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany. LA - eng PT - Journal Article DEP - 20210430 PL - Switzerland TA - Antioxidants (Basel) JT - Antioxidants (Basel, Switzerland) JID - 101668981 PMC - PMC8145035 OTO - NOTNLM OT - brain insulin signaling OT - fatty acid metabolism OT - mitochondria OT - oxidative stress COIS- The authors declare no conflict of interest. EDAT- 2021/05/06 06:00 MHDA- 2021/05/06 06:01 PMCR- 2021/04/30 CRDT- 2021/05/05 01:01 PHST- 2021/03/24 00:00 [received] PHST- 2021/04/23 00:00 [revised] PHST- 2021/04/28 00:00 [accepted] PHST- 2021/05/05 01:01 [entrez] PHST- 2021/05/06 06:00 [pubmed] PHST- 2021/05/06 06:01 [medline] PHST- 2021/04/30 00:00 [pmc-release] AID - antiox10050711 [pii] AID - antioxidants-10-00711 [pii] AID - 10.3390/antiox10050711 [doi] PST - epublish SO - Antioxidants (Basel). 2021 Apr 30;10(5):711. doi: 10.3390/antiox10050711.