TY  - GEN
A1  - Wardelmann, Kristina
A1  - Rath, Michaela
A1  - Castro, José Pedro
A1  - Blümel, Sabine
A1  - Schell, Mareike
A1  - Hauffe, Robert
A1  - Schumacher, Fabian
A1  - Flore, Tanina
A1  - Ritter, Katrin
A1  - Wernitz, Andreas
A1  - Hosoi, Toru
A1  - Ozawa, Koichiro
A1  - Kleuser, Burkhard
A1  - Weiß, Jürgen
A1  - Schürmann, Annette
A1  - Kleinridders, André
T1  - Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1165 
KW  - brain insulin signaling
KW  - mitochondria
KW  - oxidative stress
KW  - fatty acid metabolism
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-522985
SN  - 1866-8372
IS  - 5
ER  - 
TY  - JOUR
A1  - Wardelmann, Kristina
A1  - Rath, Michaela
A1  - Castro, José Pedro
A1  - Blümel, Sabine
A1  - Schell, Mareike
A1  - Hauffe, Robert
A1  - Schumacher, Fabian
A1  - Flore, Tanina
A1  - Ritter, Katrin
A1  - Wernitz, Andreas
A1  - Hosoi, Toru
A1  - Ozawa, Koichiro
A1  - Kleuser, Burkhard
A1  - Weiß, Jürgen
A1  - Schürmann, Annette
A1  - Kleinridders, André
T1  - Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus
JF  - Antioxidants
N2  - 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.
KW  - brain insulin signaling
KW  - mitochondria
KW  - oxidative stress
KW  - fatty acid metabolism
Y1  - 2021
U6  - https://doi.org/10.3390/antiox10050711
SN  - 2076-3921
VL  - 10
IS  - 5
PB  - MDPI
CY  - Basel
ER  -