TY - JOUR A1 - Vogel, Heike A1 - Kamitz, Anne A1 - Hallahan, Nicole A1 - Lebek, Sandra A1 - Schallschmidt, Tanja A1 - Jonas, Wenke A1 - Jähnert, Markus A1 - Gottmann, Pascal A1 - Zellner, Lisa A1 - Kanzleiter, Timo A1 - Damen, Mareike A1 - Altenhofen, Delsi A1 - Burkhardt, Ralph A1 - Renner, Simone A1 - Dahlhoff, Maik A1 - Wolf, Eckhard A1 - Müller, Timo Dirk A1 - Blüher, Matthias A1 - Joost, Hans-Georg A1 - Chadt, Alexandra A1 - Al-Hasani, Hadi A1 - Schürmann, Annette T1 - A collective diabetes cross in combination with a computational framework to dissect the genetics of human obesity and Type 2 diabetes JF - Human molecular genetics N2 - To explore the genetic determinants of obesity and Type 2 diabetes (T2D), the German Center for Diabetes Research (DZD) conducted crossbreedings of the obese and diabetes-prone New Zealand Obese mouse strain with four different lean strains (B6, DBA, C3H, 129P2) that vary in their susceptibility to develop T2D. Genome-wide linkage analyses localized more than 290 quantitative trait loci (QTL) for obesity, 190 QTL for diabetes-related traits and 100 QTL for plasma metabolites in the out-cross populations. A computational framework was developed that allowed to refine critical regions and to nominate a small number of candidate genes by integrating reciprocal haplotype mapping and transcriptome data. The efficiency of the complex procedure was demonstrated for one obesity QTL. The genomic interval of 35 Mb with 502 annotated candidate genes was narrowed down to six candidates. Accordingly, congenic mice retained the obesity phenotype owing to an interval that contains three of the six candidate genes. Among these the phospholipase PLA2G4A exhibited an elevated expression in adipose tissue of obese human subjects and is therefore a critical regulator of the obesity locus. Together, our broad and complex approach demonstrates that combined- and comparative-cross analysis exhibits improved mapping resolution and represents a valid tool for the identification of disease genes. Y1 - 2018 U6 - https://doi.org/10.1093/hmg/ddy217 SN - 0964-6906 SN - 1460-2083 VL - 27 IS - 17 SP - 3099 EP - 3112 PB - Oxford Univ. Press CY - Oxford ER - TY - GEN A1 - Henkel, Janin A1 - Coleman Mac Gregor of Inneregny, Charles Dominic A1 - Schraplau, Anne A1 - Jöhrens, Korinna A1 - Weiss, Thomas Siegfried A1 - Jonas, Wenke A1 - Schürmann, Annette A1 - Püschel, Gerhard Paul T1 - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 483 KW - suppress VLDL secretion KW - mice lacking KW - nonalcoholic steatohepatthis KW - insulin-resistance KW - rat hepatocytes KW - kupffer cells KW - E-2 KW - disease KW - expression KW - accumulation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-420879 SN - 1866-8372 IS - 483 ER - TY - JOUR A1 - Henkel, Janin A1 - Coleman Mac Gregor of Inneregny, Charles Dominic A1 - Schraplau, Anne A1 - Jöhrens, Korinna A1 - Weiss, Thomas Siegfried A1 - Jonas, Wenke A1 - Schürmann, Annette A1 - Püschel, Gerhard Paul T1 - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model JF - Scientific Reports N2 - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH. KW - suppress VLDL secretion KW - mice lacking KW - nonalcoholic steatohepatthis KW - insulin-resistance KW - rat hepatocytes KW - kupffer cells KW - E-2 KW - disease KW - expression KW - accumulation Y1 - 2018 U6 - https://doi.org/10.1038/s41598-018-34633-y SN - 2045-2322 IS - 8 SP - 1 EP - 11 PB - Nature Research CY - London ER - TY - JOUR A1 - Henkel, Janin A1 - Coleman, Charles Dominic A1 - Schraplau, Anne A1 - Joehrens, Korinna A1 - Weiss, Thomas Siegfried A1 - Jonas, Wenke A1 - Schürmann, Annette A1 - Püschel, Gerhard Paul T1 - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model JF - Scientific reports N2 - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH. Y1 - 2018 U6 - https://doi.org/10.1038/s41598-018-34633-y SN - 2045-2322 VL - 8 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Laeger, Thomas A1 - Castano-Martinez, Teresa A1 - Werno, Martin W. A1 - Japtok, Lukasz A1 - Baumeier, Christian A1 - Jonas, Wenke A1 - Kleuser, Burkhard A1 - Schürmann, Annette T1 - Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) N2 - Aims/hypothesis Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. Methods We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ%; CON) or low (4 kJ%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Results Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Conclusion/interpretation Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se. KW - Energy expenditure KW - FGF21 KW - Hyperglycaemia KW - Insulin resistance KW - NZO KW - Obesity KW - Protein restriction Y1 - 2018 U6 - https://doi.org/10.1007/s00125-018-4595-1 SN - 0012-186X SN - 1432-0428 VL - 61 IS - 6 SP - 1459 EP - 1469 PB - Springer CY - New York ER - TY - JOUR A1 - Jonas, Wenke A1 - Schürmann, Annette T1 - Genetic and epigenetic factors determining NAFLD risk JF - Molecular metabolism N2 - Background: Hepatic steatosis is a common chronic liver disease that can progress into more severe stages of NAFLD or promote the development of life-threatening secondary diseases for some of those affected. These include the liver itself (nonalcoholic steatohepatitis or NASH; fibrosis and cirrhosis, and hepatocellular carcinoma) or other organs such as the vessels and the heart (cardiovascular disease) or the islets of Langerhans (type 2 diabetes). In addition to elevated caloric intake and a sedentary lifestyle, genetic and epigenetic predisposition contribute to the development of NAFLD and the secondary diseases. Scope of review: We present data from genome-wide association studies (GWAS) and functional studies in rodents which describe polymorphisms identified in genes relevant for the disease as well as changes caused by altered DNA methylation and gene regulation via specific miRNAs. The review also provides information on the current status of the use of genetic and epigenetic factors as risk markers. Major conclusion: With our overview we provide an insight into the genetic and epigenetic landscape of NAFLD and argue about the applicability of currently defined risk scores for risk stratification and conclude that further efforts are needed to make the scores more usable and meaningful. KW - NAFLD KW - genetic variants KW - epigenetics KW - risk score Y1 - 2020 U6 - https://doi.org/10.1016/j.molmet.2020.101111 SN - 2212-8778 VL - 50 PB - Elsevier CY - Amsterdam ER - TY - GEN A1 - Hauffe, Robert A1 - Rath, Michaela A1 - Schell, Mareike A1 - Ritter, Katrin A1 - Kappert, Kai A1 - Deubel, Stefanie A1 - Ott, Christiane A1 - Jähnert, Markus A1 - Jonas, Wenke A1 - Schürmann, Annette A1 - Kleinridders, André T1 - HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Objective Insulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance. Methods Control and heterozygous whole-body HSP60 knockout (Hsp60+/−) mice were fed a high-fat diet (HFD, 60% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis. Results Male Hsp60+/− mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60+/− mice in a glucose tolerance test. However, Hsp60+/− mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance. Conclusions We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1235 KW - Mitochondria KW - Stress response KW - Obesity KW - Glucose homeostasis KW - Insulin resistance KW - Adipose tissue Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-548002 SN - 1866-8372 SP - 1 EP - 14 PB - Universitätsverlag Potsdam CY - Potsdam ER - TY - JOUR A1 - Hauffe, Robert A1 - Rath, Michaela A1 - Schell, Mareike A1 - Ritter, Katrin A1 - Kappert, Kai A1 - Deubel, Stefanie A1 - Ott, Christiane A1 - Jähnert, Markus A1 - Jonas, Wenke A1 - Schürmann, Annette A1 - Kleinridders, André T1 - HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue JF - Molecular Metabolism N2 - Objective Insulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance. Methods Control and heterozygous whole-body HSP60 knockout (Hsp60+/−) mice were fed a high-fat diet (HFD, 60% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis. Results Male Hsp60+/− mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60+/− mice in a glucose tolerance test. However, Hsp60+/− mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance. Conclusions We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance. KW - Mitochondria KW - Stress response KW - Obesity KW - Glucose homeostasis KW - Insulin resistance KW - Adipose tissue Y1 - 2021 U6 - https://doi.org/10.1016/j.molmet.2021.101276 SN - 2212-8778 VL - 53 SP - 1 EP - 14 PB - Elsevier CY - Amsterdam, Niederlande ER - TY - JOUR A1 - Jonas, Wenke A1 - Kluth, Oliver A1 - Helms, Anett A1 - Voss, Sarah A1 - Jahnert, Markus A1 - Gottmann, Pascal A1 - Speckmann, Thilo A1 - Knebel, Birgit A1 - Chadt, Alexandra A1 - Al-Hasani, Hadi A1 - Schürmann, Annette A1 - Vogel, Heike T1 - Identification of novel genes involved in hyperglycemia in mice JF - International journal of molecular sciences N2 - Current attempts to prevent and manage type 2 diabetes have been moderately effective, and a better understanding of the molecular roots of this complex disease is important to develop more successful and precise treatment options. Recently, we initiated the collective diabetes cross, where four mouse inbred strains differing in their diabetes susceptibility were crossed with the obese and diabetes-prone NZO strain and identified the quantitative trait loci (QTL) Nidd13/NZO, a genomic region on chromosome 13 that correlates with hyperglycemia in NZO allele carriers compared to B6 controls. Subsequent analysis of the critical region, harboring 644 genes, included expression studies in pancreatic islets of congenic Nidd13/NZO mice, integration of single-cell data from parental NZO and B6 islets as well as haplotype analysis. Finally, of the five genes (Acot12, S100z, Ankrd55, Rnf180, and Iqgap2) within the polymorphic haplotype block that are differently expressed in islets of B6 compared to NZO mice, we identified the calcium-binding protein S100z gene to affect islet cell proliferation as well as apoptosis when overexpressed in MINE cells. In summary, we define S100z as the most striking gene to be causal for the diabetes QTL Nidd13/NZO by affecting beta-cell proliferation and apoptosis. Thus, S100z is an entirely novel diabetes gene regulating islet cell function. KW - beta-cell KW - diabetes KW - proliferation KW - apoptosis KW - QTL Y1 - 2022 U6 - https://doi.org/10.3390/ijms23063205 SN - 1661-6596 SN - 1422-0067 VL - 23 IS - 6 PB - MDPI CY - Basel ER - TY - JOUR A1 - Graja, Antonia A1 - Garcia-Carrizo, Francisco A1 - Jank, Anne-Marie A1 - Gohlke, Sabrina A1 - Ambrosi, Thomas H. A1 - Jonas, Wenke A1 - Ussar, Siegfried A1 - Kern, Matthias A1 - Schürmann, Annette A1 - Aleksandrova, Krasimira A1 - Bluher, Matthias A1 - Schulz, Tim Julius T1 - Loss of periostin occurs in aging adipose tissue of mice and its genetic ablation impairs adipose tissue lipid metabolism JF - Aging Cell N2 - Remodeling of the extracellular matrix is a key component of the metabolic adaptations of adipose tissue in response to dietary and physiological challenges. Disruption of its integrity is a well-known aspect of adipose tissue dysfunction, for instance, during aging and obesity. Adipocyte regeneration from a tissue-resident pool of mesenchymal stem cells is part of normal tissue homeostasis. Among the pathophysiological consequences of adipogenic stem cell aging, characteristic changes in the secretory phenotype, which includes matrix-modifying proteins, have been described. Here, we show that the expression of the matricellular protein periostin, a component of the extracellular matrix produced and secreted by adipose tissue-resident interstitial cells, is markedly decreased in aged brown and white adipose tissue depots. Using a mouse model, we demonstrate that the adaptation of adipose tissue to adrenergic stimulation and high-fat diet feeding is impaired in animals with systemic ablation of the gene encoding for periostin. Our data suggest that loss of periostin attenuates lipid metabolism in adipose tissue, thus recapitulating one aspect of age-related metabolic dysfunction. In human white adipose tissue, periostin expression showed an unexpected positive correlation with age of study participants. This correlation, however, was no longer evident after adjusting for BMI or plasma lipid and liver function biomarkers. These findings taken together suggest that age-related alterations of the adipose tissue extracellular matrix may contribute to the development of metabolic disease by negatively affecting nutrient homeostasis. KW - adipogenic progenitor cells KW - adipose tissue KW - aging KW - extracellular matrix KW - fatty acid metabolism KW - periostin Y1 - 2018 U6 - https://doi.org/10.1111/acel.12810 SN - 1474-9718 SN - 1474-9726 VL - 17 IS - 5 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Hauffe, Robert A1 - Rath, Michaela A1 - Agyapong, Wilson A1 - Jonas, Wenke A1 - Vogel, Heike A1 - Schulz, Tim Julius A1 - Schwarz, Maria A1 - Kipp, Anna Patricia A1 - Blüher, Matthias A1 - Kleinridders, André T1 - Obesity Hinders the Protective Effect of Selenite Supplementation on Insulin Signaling JF - Antioxidants N2 - The intake of high-fat diets (HFDs) containing large amounts of saturated long-chain fatty acids leads to obesity, oxidative stress, inflammation, and insulin resistance. The trace element selenium, as a crucial part of antioxidative selenoproteins, can protect against the development of diet-induced insulin resistance in white adipose tissue (WAT) by increasing glutathione peroxidase 3 (GPx3) and insulin receptor (IR) expression. Whether selenite (Se) can attenuate insulin resistance in established lipotoxic and obese conditions is unclear. We confirm that GPX3 mRNA expression in adipose tissue correlates with BMI in humans. Cultivating 3T3-L1 pre-adipocytes in palmitate-containing medium followed by Se treatment attenuates insulin resistance with enhanced GPx3 and IR expression and adipocyte differentiation. However, feeding obese mice a selenium-enriched high-fat diet (SRHFD) only resulted in a modest increase in overall selenoprotein gene expression in WAT in mice with unaltered body weight development, glucose tolerance, and insulin resistance. While Se supplementation improved adipocyte morphology, it did not alter WAT insulin sensitivity. However, mice fed a SRHFD exhibited increased insulin content in the pancreas. Overall, while selenite protects against palmitate-induced insulin resistance in vitro, obesity impedes the effect of selenite on insulin action and adipose tissue metabolism in vivo. KW - selenite KW - insulin KW - adipose tissue KW - obesity KW - insulin resistance Y1 - 2022 U6 - https://doi.org/10.3390/antiox11050862 SN - 2076-3921 VL - 11 SP - 1 EP - 16 PB - MDPI CY - Basel, Schweiz ET - 5 ER - TY - GEN A1 - Hauffe, Robert A1 - Rath, Michaela A1 - Agyapong, Wilson A1 - Jonas, Wenke A1 - Vogel, Heike A1 - Schulz, Tim Julius A1 - Schwarz, Maria A1 - Kipp, Anna Patricia A1 - Blüher, Matthias A1 - Kleinridders, André T1 - Obesity Hinders the Protective Effect of Selenite Supplementation on Insulin Signaling T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - The intake of high-fat diets (HFDs) containing large amounts of saturated long-chain fatty acids leads to obesity, oxidative stress, inflammation, and insulin resistance. The trace element selenium, as a crucial part of antioxidative selenoproteins, can protect against the development of diet-induced insulin resistance in white adipose tissue (WAT) by increasing glutathione peroxidase 3 (GPx3) and insulin receptor (IR) expression. Whether selenite (Se) can attenuate insulin resistance in established lipotoxic and obese conditions is unclear. We confirm that GPX3 mRNA expression in adipose tissue correlates with BMI in humans. Cultivating 3T3-L1 pre-adipocytes in palmitate-containing medium followed by Se treatment attenuates insulin resistance with enhanced GPx3 and IR expression and adipocyte differentiation. However, feeding obese mice a selenium-enriched high-fat diet (SRHFD) only resulted in a modest increase in overall selenoprotein gene expression in WAT in mice with unaltered body weight development, glucose tolerance, and insulin resistance. While Se supplementation improved adipocyte morphology, it did not alter WAT insulin sensitivity. However, mice fed a SRHFD exhibited increased insulin content in the pancreas. Overall, while selenite protects against palmitate-induced insulin resistance in vitro, obesity impedes the effect of selenite on insulin action and adipose tissue metabolism in vivo. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1267 KW - selenite KW - insulin KW - adipose tissue KW - obesity KW - insulin resistance Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-561709 SN - 1866-8372 SP - 1 EP - 16 PB - Universitätsverlag Potsdam CY - Potsdam ER - TY - JOUR A1 - Kehm, Richard A1 - Jähnert, Markus A1 - Deubel, Stefanie A1 - Flore, Tanina A1 - König, Jeannette A1 - Jung, Tobias A1 - Stadion, Mandy A1 - Jonas, Wenke A1 - Schürmann, Annette A1 - Grune, Tilman A1 - Höhn, Annika T1 - Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: role of thioredoxin-interacting protein (TXNIP) JF - Redox Biology N2 - Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetesprone NZO mice. KW - aging KW - redox homeostasis KW - metabolic stress KW - beta-cells KW - cell cycle KW - thioredoxin-interacting protein Y1 - 2020 U6 - https://doi.org/10.1016/j.redox.2020.101748 SN - 2213-2317 VL - 37 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Henkel, Janin A1 - Alfine, Eugenia A1 - Saín, Juliana A1 - Jöhrens, Korinna A1 - Weber, Daniela A1 - Castro, José Pedro A1 - König, Jeannette A1 - Stuhlmann, Christin A1 - Vahrenbrink, Madita A1 - Jonas, Wenke A1 - Kleinridders, André A1 - Püschel, Gerhard Paul T1 - Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol JF - Nutrients N2 - While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease. KW - non-alcoholic fatty liver disease (NAFLD) KW - NASH KW - cholesterol KW - PUFA KW - inflammation KW - oxidative stress Y1 - 2018 U6 - https://doi.org/10.3390/nu10091326 SN - 2072-6643 VL - 10 IS - 9 SP - 1 EP - 17 PB - Molecular Diversity Preservation International (MDPI) CY - Basel ER - TY - GEN A1 - Henkel, Janin A1 - Alfine, Eugenia A1 - Saín, Juliana A1 - Jöhrens, Korinna A1 - Weber, Daniela A1 - Castro, José Pedro A1 - König, Jeannette A1 - Stuhlmann, Christin A1 - Vahrenbrink, Madita A1 - Jonas, Wenke A1 - Kleinridders, André A1 - Püschel, Gerhard Paul T1 - Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol T2 - Nutrients N2 - While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 479 KW - non-alcoholic fatty liver disease (NAFLD) KW - NASH KW - cholesterol KW - PUFA KW - inflammation KW - oxidative stress Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-419773 ER -