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  - 
TY  - GEN
A1  - Nicolai, Merle Marie
A1  - Weishaupt, Ann-Kathrin
A1  - Baesler, Jessica
A1  - Brinkmann, Vanessa
A1  - Wellenberg, Anna
A1  - Winkelbeiner, Nicola Lisa
A1  - Gremme, Anna
A1  - Aschner, Michael
A1  - Fritz, Gerhard
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Effects of manganese on genomic integrity in the multicellular model organism Caenorhabditis elegans
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Although manganese (Mn) is an essential trace element, overexposure is associated with Mn-induced toxicity and neurological dysfunction. Even though Mn-induced oxidative stress is discussed extensively, neither the underlying mechanisms of the potential consequences of Mn-induced oxidative stress on DNA damage and DNA repair, nor the possibly resulting toxicity are characterized yet. In this study, we use the model organism Caenorhabditis elegans to investigate the mode of action of Mn toxicity, focusing on genomic integrity by means of DNA damage and DNA damage response. Experiments were conducted to analyze Mn bioavailability, lethality, and induction of DNA damage. Different deletion mutant strains were then used to investigate the role of base excision repair (BER) and dePARylation (DNA damage response) proteins in Mn-induced toxicity. The results indicate a dose- and time-dependent uptake of Mn, resulting in increased lethality. Excessive exposure to Mn decreases genomic integrity and activates BER. Altogether, this study characterizes the consequences of Mn exposure on genomic integrity and therefore broadens the molecular understanding of pathways underlying Mn-induced toxicity. Additionally, studying the basal poly(ADP-ribosylation) (PARylation) of worms lacking poly(ADP-ribose) glycohydrolase (PARG) parg-1 or parg-2 (two orthologue of PARG), indicates that parg-1 accounts for most of the glycohydrolase activity in worms.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1173 
KW  - manganese
KW  - oxidative stress
KW  - DNA repair
KW  - DNA damage response
KW  - Caenorhabditis elegans
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-523275
SN  - 1866-8372
IS  - 1173
ER  - 
TY  - JOUR
A1  - Nicolai, Merle Marie
A1  - Weishaupt, Ann-Kathrin
A1  - Baesler, Jessica
A1  - Brinkmann, Vanessa
A1  - Wellenberg, Anna
A1  - Winkelbeiner, Nicola Lisa
A1  - Gremme, Anna
A1  - Aschner, Michael
A1  - Fritz, Gerhard
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Effects of manganese on genomic integrity in the multicellular model organism Caenorhabditis elegans
JF  - International Journal of Molecular Sciences
N2  - Although manganese (Mn) is an essential trace element, overexposure is associated with Mn-induced toxicity and neurological dysfunction. Even though Mn-induced oxidative stress is discussed extensively, neither the underlying mechanisms of the potential consequences of Mn-induced oxidative stress on DNA damage and DNA repair, nor the possibly resulting toxicity are characterized yet. In this study, we use the model organism Caenorhabditis elegans to investigate the mode of action of Mn toxicity, focusing on genomic integrity by means of DNA damage and DNA damage response. Experiments were conducted to analyze Mn bioavailability, lethality, and induction of DNA damage. Different deletion mutant strains were then used to investigate the role of base excision repair (BER) and dePARylation (DNA damage response) proteins in Mn-induced toxicity. The results indicate a dose- and time-dependent uptake of Mn, resulting in increased lethality. Excessive exposure to Mn decreases genomic integrity and activates BER. Altogether, this study characterizes the consequences of Mn exposure on genomic integrity and therefore broadens the molecular understanding of pathways underlying Mn-induced toxicity. Additionally, studying the basal poly(ADP-ribosylation) (PARylation) of worms lacking poly(ADP-ribose) glycohydrolase (PARG) parg-1 or parg-2 (two orthologue of PARG), indicates that parg-1 accounts for most of the glycohydrolase activity in worms.
KW  - manganese
KW  - oxidative stress
KW  - DNA repair
KW  - DNA damage response
KW  - Caenorhabditis elegans
Y1  - 2021
U6  - https://doi.org/10.3390/ijms222010905
SN  - 1422-0067
VL  - 22
IS  - 20
PB  - MDPI
CY  - Basel
ER  -