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 - Schäfer, Marjänn Helena A1 - Kakularam, Kumar Reddy A1 - Reisch, Florian A1 - Rothe, Michael A1 - Stehling, Sabine A1 - Heydeck, Dagmar A1 - Püschel, Gerhard Paul A1 - Kuhn, Hartmut T1 - Male Knock-in Mice Expressing an Arachidonic Acid Lipoxygenase 15B (Alox15B) with Humanized Reaction Specificity Are Prematurely Growth Arrested When Aging T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in cell differentiation and in the pathogenesis of inflammation. The mouse genome involves seven functional Alox genes and the encoded enzymes share a high degree of amino acid conservation with their human orthologs. There are, however, functional differences between mouse and human ALOX orthologs. Human ALOX15B oxygenates arachidonic acid exclusively to its 15-hydroperoxy derivative (15S-HpETE), whereas 8S-HpETE is dominantly formed by mouse Alox15b. The structural basis for this functional difference has been explored and in vitro mutagenesis humanized the reaction specificity of the mouse enzyme. To explore whether this mutagenesis strategy may also humanize the reaction specificity of mouse Alox15b in vivo, we created Alox15b knock-in mice expressing the arachidonic acid 15-lipoxygenating Tyr603Asp+His604Val double mutant instead of the 8-lipoxygenating wildtype enzyme. These mice are fertile, display slightly modified plasma oxylipidomes and develop normally up to an age of 24 weeks. At later developmental stages, male Alox15b-KI mice gain significantly less body weight than outbred wildtype controls, but this effect was not observed for female individuals. To explore the possible reasons for the observed gender-specific growth arrest, we determined the basic hematological parameters and found that aged male Alox15b-KI mice exhibited significantly attenuated red blood cell parameters (erythrocyte counts, hematocrit, hemoglobin). Here again, these differences were not observed in female individuals. These data suggest that humanization of the reaction specificity of mouse Alox15b impairs the functionality of the hematopoietic system in males, which is paralleled by a premature growth arrest. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1295 KW - eicosanoids KW - lipid peroxidation KW - oxidative stress KW - polyenoic fatty acids KW - erythropoiesis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-576491 SN - 1866-8372 IS - 1295 ER - TY - JOUR A1 - Schäfer, Marjänn Helena A1 - Kakularam, Kumar Reddy A1 - Reisch, Florian A1 - Rothe, Michael A1 - Stehling, Sabine A1 - Heydeck, Dagmar A1 - Püschel, Gerhard Paul A1 - Kuhn, Hartmut T1 - Male Knock-in Mice Expressing an Arachidonic Acid Lipoxygenase 15B (Alox15B) with Humanized Reaction Specificity Are Prematurely Growth Arrested When Aging JF - Biomedicines N2 - Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in cell differentiation and in the pathogenesis of inflammation. The mouse genome involves seven functional Alox genes and the encoded enzymes share a high degree of amino acid conservation with their human orthologs. There are, however, functional differences between mouse and human ALOX orthologs. Human ALOX15B oxygenates arachidonic acid exclusively to its 15-hydroperoxy derivative (15S-HpETE), whereas 8S-HpETE is dominantly formed by mouse Alox15b. The structural basis for this functional difference has been explored and in vitro mutagenesis humanized the reaction specificity of the mouse enzyme. To explore whether this mutagenesis strategy may also humanize the reaction specificity of mouse Alox15b in vivo, we created Alox15b knock-in mice expressing the arachidonic acid 15-lipoxygenating Tyr603Asp+His604Val double mutant instead of the 8-lipoxygenating wildtype enzyme. These mice are fertile, display slightly modified plasma oxylipidomes and develop normally up to an age of 24 weeks. At later developmental stages, male Alox15b-KI mice gain significantly less body weight than outbred wildtype controls, but this effect was not observed for female individuals. To explore the possible reasons for the observed gender-specific growth arrest, we determined the basic hematological parameters and found that aged male Alox15b-KI mice exhibited significantly attenuated red blood cell parameters (erythrocyte counts, hematocrit, hemoglobin). Here again, these differences were not observed in female individuals. These data suggest that humanization of the reaction specificity of mouse Alox15b impairs the functionality of the hematopoietic system in males, which is paralleled by a premature growth arrest. KW - eicosanoids KW - lipid peroxidation KW - oxidative stress KW - polyenoic fatty acids KW - erythropoiesis Y1 - 2022 U6 - https://doi.org/10.3390/biomedicines10061379 SN - 2227-9059 VL - 10 SP - 1 EP - 22 PB - MDPI CY - Basel, Schweiz ET - 6 ER - TY - JOUR A1 - Rohn, Isabelle A1 - Raschke, Stefanie A1 - Aschner, Michael A1 - Tuck, Simon A1 - Kuehnelt, Doris A1 - Kipp, Anna Patricia A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Treatment of caenorhabditis elegans with small selenium species enhances antioxidant defense systems JF - Molecular nutrition & food research : bioactivity, chemistry, immunology, microbiology, safety, technology N2 - ScopeSmall selenium (Se) species play a key role in Se metabolism and act as dietary sources of the essential trace element. However, they are redox-active and trigger pro- and antioxidant responses. As health outcomes are strongly species-dependent, species-specific characteristics of Se compounds are tested in vivo. Methods and resultsIn the model organism Caenorhabditis elegans (C. elegans), immediate and sustained effects of selenite, selenomethionine (SeMet), and Se-methylselenocysteine (MeSeCys) are studied regarding their bioavailability, incorporation into proteins, as well as modulation of the cellular redox status. While all tested Se compounds are bioavailable, only SeMet persistently accumulates and is non-specifically incorporated into proteins. However, the protection toward chemically-induced formation of reactive species is independent of the applied Se compound. Increased thioredoxin reductase (TXNRD) activity and changes in mRNA expression levels of antioxidant proteins indicate the activation of cellular defense mechanisms. However, in txnrd-1 deletion mutants, no protective effects of the Se species are observed anymore, which is also reflected by differential gene expression data. ConclusionSe species protect against chemically-induced reactive species formation. The identified immediate and sustained systemic effects of Se species give rise to speculations on possible benefits facing subsequent periods of inadequate Se intake. KW - antioxidant defense systems KW - caenorhabditis elegans KW - selenium KW - oxidative stress KW - selenoproteins Y1 - 2019 U6 - https://doi.org/10.1002/mnfr.201801304 SN - 1613-4125 SN - 1613-4133 VL - 63 IS - 9 PB - Wiley CY - Hoboken ER - TY - THES A1 - Kochlik, Bastian Max T1 - Relevance of biomarkers for the diagnosis of the frailty syndrome T1 - Die Bedeutung von Biomarkern für die Diagnose des Frailty-Syndroms BT - focus on parameters of muscle protein turnover, micronutrients and oxidative stress BT - 3-Methylhistidine, Mikronährstoffe und oxidativer Stress im Fokus N2 - Frailty and sarcopenia share some underlying characteristics like loss of muscle mass, low muscle strength, and low physical performance. Imaging parameters and functional examinations mainly assess frailty and sarcopenia criteria; however, these measures can have limitations in clinical settings. Therefore, finding suitable biomarkers that reflect a catabolic muscle state e.g. an elevated muscle protein turnover as suggested in frailty, are becoming more relevant concerning frailty diagnosis and risk assessment. 3-Methylhistidine (3-MH) and its ratios 3-MH-to-creatinine (3-MH/Crea) and 3 MH-to-estimated glomerular filtration rate (3-MH/eGFR) are under discussion as possible biomarkers for muscle protein turnover and might support the diagnosis of frailty. However, there is some skepticism about the reliability of 3-MH measures since confounders such as meat and fish intake might influence 3-MH plasma concentrations. Therefore, the influence of dietary habits and an intervention with white meat on plasma 3-MH was determined in young and healthy individuals. In another study, the cross-sectional associations of plasma 3-MH, 3-MH/Crea and 3-MH/eGFR with the frailty status (robust, pre-frail and frail) were investigated. Oxidative stress (OS) is a possible contributor to frailty development, and high OS levels as well as low micronutrient levels are associated with the frailty syndrome. However, data on simultaneous measures of OS biomarkers together with micronutrients are lacking in studies including frail, pre-frail and robust individuals. Therefore, cross-sectional associations of protein carbonyls (PrCarb), 3-nitrotyrosine (3-NT) and several micronutrients with the frailty status were determined. A validated UPLC-MS/MS (ultra-performance liquid chromatography tandem mass spectrometry) method for the simultaneous quantification of 3-MH and 1-MH (1 methylhistidine, as marker for meat and fish consumption) was presented and used for further analyses. Omnivores showed higher plasma 3-MH and 1-MH concentrations than vegetarians and a white meat intervention resulted in an increase in plasma 3-MH, 3 MH/Crea, 1-MH and 1-MH/Crea in omnivores. Elevated 3-MH and 3-MH/Crea levels declined significantly within 24 hours after this white meat intervention. Thus, 3-MH and 3-MH/Crea might be used as biomarker for muscle protein turnover when subjects did not consume meat 24 hours prior to blood samplings. Plasma 3-MH, 3-MH/Crea and 3-MH/eGFR were higher in frail individuals than in robust individuals. Additionally, these biomarkers were positively associated with frailty in linear regression models, and higher odds to be frail were found for every increase in 3 MH and 3-MH/eGFR quintile in multivariable logistic regression models adjusted for several confounders. This was the first study using 3-MH/eGFR and it is concluded that plasma 3-MH, 3-MH/Crea and 3-MH/eGFR might be used to identify frail individuals or individuals at higher risk to be frail, and that there might be threshold concentrations or ratios to support these diagnoses. Higher vitamin D3, lutein/zeaxanthin, γ-tocopherol, α-carotene, β-carotene, lycopene and β-cryptoxanthin concentrations and additionally lower PrCarb concentrations were found in robust compared to frail individuals in multivariate linear models. Frail subjects had higher odds to be in the lowest than in the highest tertile for vitamin D3 α-tocopherol, α-carotene, β-carotene, lycopene, lutein/zeaxanthin, and β cryptoxanthin, and had higher odds to be in the highest than in the lowest tertile for PrCarb than robust individuals in multivariate logistic regression models. Thus, a low micronutrient together with a high PrCarb status is associated with pre-frailty and frailty. N2 - Gebrechlichkeit (englisch: frailty) und Sarkopenie teilen einige zugrundeliegende Merkmale wie einen Verlust von Muskelmasse, eine geringe Muskelkraft und eine geringe körperliche Leistungsfähigkeit, welche durch einen erhöhten Muskelproteinumsatz entstehen können. Kriterien der Gebrechlichkeit und Sarkopenie werden hauptsächlich durch bildgebende Verfahren sowie funktionelle Untersuchungen gemessen, die in ihrer Durchführbarkeit im klinischen Alltag jedoch eingeschränkt sein können. Daher gewinnt das Finden geeigneter Biomarker zur Anzeige eines erhöhten Muskelproteinumsatzes (kataboler Muskelzustand) in Bezug auf Diagnose und Risikobewertung der Gebrechlichkeit zunehmend an Bedeutung. 3-Methylhistidin (3-MH) und die Verhältnisse 3-MH zu Kreatinin (3-MH/Crea) und 3-MH zu geschätzter glomerulärer Filtrationsrate (3-MH/eGFR) werden als solche möglichen Biomarker diskutiert und könnten folglich die Diagnose und Risikobewertung von Gebrechlichkeit unterstützen. Es herrscht jedoch eine gewisse Skepsis hinsichtlich der Zuverlässigkeit von 3-MH-Messungen, da 3-MH-Plasmakonzentrationen durch Fleisch- und Fischaufnahme beeinflusst werden können. Daher wurde der Einfluss von Ernährungsgewohnheiten (Mischkost oder vegetarisch) und einer Intervention mit Hähnchenfleisch auf Plasma-3-MH bei jungen und gesunden Personen untersucht. In einer weiteren Studie wurden die Querschnittsassoziationen von 3-MH, 3-MH/Crea und 3-MH/eGFR im Plasma mit dem Frailty-Status (robust, pre-frail und frail) untersucht. Oxidativer Stress (OS) ist ein potentieller Faktor der zur Entwicklung von Gebrechlichkeit beiträgt, und sowohl hohe OS-Konzentrationen als auch niedrige Mikronährstoffkonzentrationen sind mit Gebrechlichkeit assoziiert. Daten zu simultanen Messungen von OS und Mikronährstoffen in Personen aller drei Frailty-Kategorien (robust, pre-frail und frail) fehlen jedoch. Aus diesem Grund wurden Querschnittsassoziationen von Proteincarbonylen (PrCarb), 3-Nitrotyrosin (3-NT) und mehrerer fettlöslicher Mikronährstoffe mit dem Frailty-Status bestimmt. Eine validierte UPLC-MS/MS-Methode (ultra-performance liquid chromatography tandem mass spectrometry) zur simultanen Bestimmung von 3-MH und 1-MH (1 Methylhistidin als Marker für den Fleisch- und Fischkonsum) in Plasma wurde beschrieben und für die weiteren Analysen verwendet. Mischköstler wiesen höhere 3 MH- und 1-MH-Konzentrationen in Plasma auf als Vegetarier. Die Intervention mit Hähnchenfleisch führte zu einem Anstieg von Plasma 3-MH, 3-MH/Crea, 1-MH und 1 MH/Crea bei Mischköstlern. Diese erhöhten 3-MH- und 3-MH/Crea-Spiegel sanken innerhalb von 24 Stunden nach der Intervention signifikant ab. Folglich stellen 3-MH und 3-MH/Crea potentielle Biomarker für den Muskelproteinumsatz dar, wenn Personen für 24 Stunden vor der Blutentnahme kein Fleisch verzehrt haben. Gebrechliche Teilnehmer wiesen höhere Plasma 3-MH-, 3-MH/Crea- und 3 MH/eGFR-Werte auf als robuste Teilnehmer und zusätzlich waren diese Biomarker in linearen Regressionsmodellen positiv mit Gebrechlichkeit assoziiert. In multivariablen logistischen Regressionsmodellen (adjustiert für mehrere Confounder) waren gebrechliche Personen im Vergleich zu robusten Personen mit einer höheren Wahrscheinlichkeit in einer höheren 3-MH- und 3-MH/eGFR-Quintile. Diese erste Studie, die 3-MH/eGFR als Biomarker für Gebrechlichkeit untersucht hat, erlaubt die Schlussfolgerung, dass Plasma-3-MH, -3-MH/Crea und -3-MH/eGFR verwendet werden könnte, um gebrechliche Personen oder Personen mit einem erhöhten Frailty-Risiko zu identifizieren. Möglicherweise gibt es auch Schwellenwerte, die diese Diagnosen unterstützen können. In multivariaten Regressionsanalysen wiesen robuste Personen höhere Vitamin D3-, Lutein/Zeaxanthin-, γ-Tocopherol-, α-Carotin-, β-Carotin-, Lycopin- und β Cryptoxanthin-Konzentrationen sowie niedrigere PrCarb-Konzentrationen auf als gebrechliche Personen. Zudem waren in multinomialen logistischen Regressionsanalysen gebrechliche Personen mit einer höheren Wahrscheinlichkeit sowohl in der niedrigsten Vitamin D3-, α-Tocopherol-, α-Carotin-, β-Carotin-, Lycopin-, Lutein/Zeaxanthin- und β Cryptoxanthin-Tertil als auch im höchsten PrCarb-Tertil zu finden als robuste Personen. Es wird daher geschlussfolgert, dass niedrige Mikronährstoffkonzentrationen zusammen mit hohen PrCarb-Konzentrationen mit Gebrechlichkeit und dessen Vorstufe (pre-frailty) assoziiert sind. KW - biomarker KW - Biomarker KW - frailty KW - Frailty KW - micronutrients KW - Mikronährstoffe KW - oxidative stress KW - oxidativer Stress KW - 3-methylhistidine KW - 3-Methylhistidin KW - muscle protein turnover KW - Muskelproteinumsatz Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-441186 ER - TY - JOUR A1 - Ijomone, Omamuyovwi M. A1 - Iroegbu, Joy D. A1 - Morcillo, Patricia A1 - Ayodele, Akinyemi J. A1 - Ijomone, Olayemi K. A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Aschner, Michael T1 - Sex-dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure JF - Environmental toxicology N2 - Manganese (Mn), although important for multiple cellular processes, has posed environmental health concerns due to its neurotoxic effects. In recent years, there have been extensive studies on the mechanism of Mn-induced neuropathology, as well as the sex-dependent vulnerability to its neurotoxic effects. Nonetheless, cellular mechanisms influenced by sex differences in susceptibility to Mn have yet to be adequately characterized. Since oxidative stress is a key mechanism of Mn neurotoxicity, here, we have probed Hsp70 and Nrf2 proteins to investigate the sex-dependent changes following exposure to Mn. Male and female rats were administered intraperitoneal injections of MnCl2 (10 mg/kg and 25 mg/kg) 48 hourly for a total of eight injections (15 days). We evaluated changes in body weight, as well as Mn accumulation, Nrf2 and Hsp70 expression across four brain regions; striatum, cortex, hippocampus and cerebellum in both sexes. Our results showed sex-specific changes in body-weight, specifically in males but not in females. Additionally, we noted sex-dependent accumulation of Mn in the brain, as well as in expression levels of Nrf2 and Hsp70 proteins. These findings revealed sex-dependent susceptibility to Mn-induced neurotoxicity corresponding to differential Mn accumulation, and expression of Hsp70 and Nrf2 across several brain regions. KW - brain KW - female KW - male KW - manganese KW - oxidative stress Y1 - 2022 U6 - https://doi.org/10.1002/tox.23583 SN - 1520-4081 SN - 1522-7278 VL - 37 IS - 9 SP - 2167 EP - 2177 PB - Wiley CY - New York, NY ER - TY - GEN A1 - Hocher, Berthold A1 - Zeng, Shufei T1 - Clear the fog around parathyroid hormone assays BT - what do iPTH assays really measure? T2 - Clinical journal of the American Society of Nephrology KW - Assays KW - Biological Assay KW - CKD KW - oxidative stress KW - PTH Y1 - 2018 U6 - https://doi.org/10.2215/CJN.01730218 SN - 1555-9041 SN - 1555-905X VL - 13 IS - 4 SP - 524 EP - 526 PB - American Society of Nephrology CY - Washington ER - TY - GEN A1 - Henkel, Janin A1 - Buchheim-Dieckow, Katja A1 - Castro, José Pedro A1 - Laeger, Thomas A1 - Wardelmann, Kristina A1 - Kleinridders, André A1 - Jöhrens, Korinna A1 - Püschel, Gerhard Paul T1 - Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Non-alcoholic fatty liver diseases (NAFLD) including the severe form with steatohepatitis (NASH) are highly prevalent ailments to which no approved pharmacological treatment exists. Dietary intervention aiming at 10% weight reduction is efficient but fails due to low compliance. Increase in physical activity is an alternative that improved NAFLD even in the absence of weight reduction. The underlying mechanisms are unclear and cannot be studied in humans. Here, a rat NAFLD model was developed that reproduces many facets of the diet-induced NAFLD in humans. The impact of endurance exercise was studied in this model. Male Wistar rats received control chow or a NASH-inducing diet rich in fat, cholesterol, and fructose. Both diet groups were subdivided into a sedentary and an endurance exercise group. Animals receiving the NASH-inducing diet gained more body weight, got glucose intolerant and developed a liver pathology with steatosis, hepatocyte hypertrophy, inflammation and fibrosis typical of NAFLD or NASH. Contrary to expectations, endurance exercise did not improve the NASH activity score and even enhanced hepatic inflammation. However, endurance exercise attenuated the hepatic cholesterol overload and the ensuing severe oxidative stress. In addition, exercise improved glucose tolerance possibly in part by induction of hepatic FGF21 production. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 807 KW - NAFLD KW - NASH KW - endurance exercise KW - FGF21 KW - glucose intolerance KW - cholesterol KW - oxidative stress Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-442384 SN - 1866-8372 IS - 807 ER - TY - JOUR A1 - Henkel, Janin A1 - Buchheim-Dieckow, Katja A1 - Castro, José Pedro A1 - Laeger, Thomas A1 - Wardelmann, Kristina A1 - Kleinridders, André A1 - Jöhrens, Korinna A1 - Püschel, Gerhard Paul T1 - Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH JF - Nutrients N2 - Non-alcoholic fatty liver diseases (NAFLD) including the severe form with steatohepatitis (NASH) are highly prevalent ailments to which no approved pharmacological treatment exists. Dietary intervention aiming at 10% weight reduction is efficient but fails due to low compliance. Increase in physical activity is an alternative that improved NAFLD even in the absence of weight reduction. The underlying mechanisms are unclear and cannot be studied in humans. Here, a rat NAFLD model was developed that reproduces many facets of the diet-induced NAFLD in humans. The impact of endurance exercise was studied in this model. Male Wistar rats received control chow or a NASH-inducing diet rich in fat, cholesterol, and fructose. Both diet groups were subdivided into a sedentary and an endurance exercise group. Animals receiving the NASH-inducing diet gained more body weight, got glucose intolerant and developed a liver pathology with steatosis, hepatocyte hypertrophy, inflammation and fibrosis typical of NAFLD or NASH. Contrary to expectations, endurance exercise did not improve the NASH activity score and even enhanced hepatic inflammation. However, endurance exercise attenuated the hepatic cholesterol overload and the ensuing severe oxidative stress. In addition, exercise improved glucose tolerance possibly in part by induction of hepatic FGF21 production. KW - NAFLD KW - NASH KW - endurance exercise KW - FGF21 KW - glucose intolerance KW - cholesterol KW - oxidative stress Y1 - 2019 U6 - https://doi.org/10.3390/nu11112709 SN - 2072-6643 VL - 11 IS - 11 PB - MDPI CY - Basel ER -