TY - JOUR A1 - Quiclet, Charline A1 - Dittberner, Nicole A1 - Gaessler, Anneke A1 - Stadion, Mandy A1 - Gerst, Felicia A1 - Helms, Anett A1 - Baumeier, Christian A1 - Schulz, Tim Julius A1 - Schurmann, Annette T1 - Pancreatic adipocytes mediate hypersecretion of insulin in diabetes-susceptible mice JF - Metabolism - Clinical and experimental N2 - Objective: Ectopic fat accumulation in the pancreas in response to obesity and its implication on the onset of type 2 diabetes remain poorly understood. Intermittent fasting (IF) is known to improve glucose homeostasis and insulin resistance. However, the effects of IF on fat in the pancreas and beta-cell function remain largely unknown. Our aim was to evaluate the impact of IF on pancreatic fat accumulation and its effects on islet function. Methods: New Zealand Obese (NZO) mice were fed a high-fat diet ad libitum (NZO-AL) or fasted every other day (intermittent fasting, NZO-IF) and pancreatic fat accumulation, glucose homoeostasis, insulin sensitivity, and islet function were determined and compared to ad libitum-fed B6.V-Lep(ob/ob) (ob/ob) mice. To investigate the crosstalk of pancreatic adipocytes and islets, co-culture experiments were performed. Results: NZO-IF mice displayed better glucose homeostasis and lower fat accumulation in both the pancreas (-32%) and the liver (-35%) than NZO-AL mice. Ob/ob animals were insulin-resistant and had low fat in the pancreas but high fat in the liver. NZO-AL mice showed increased fat accumulation in both organs and exhibited an impaired islet function. Co-culture experiments demonstrated that pancreatic adipocytes induced a hypersecretion of insulin and released higher levels of free fatty adds than adipocytes of inguinal white adipose tissue. Conclusions: These results suggest that pancreatic fat participates in diabetes development, but can be prevented by IF. (C) 2019 Published by Elsevier Inc. Y1 - 2019 U6 - https://doi.org/10.1016/j.metabol.2019.05.005 SN - 0026-0495 SN - 1532-8600 VL - 97 SP - 9 EP - 17 PB - Elsevier CY - Philadelphia 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 - JOUR A1 - Krstic, Jelena A1 - Reinisch, Isabel A1 - Schupp, Michael A1 - Schulz, Tim Julius A1 - Prokesch, Andreas T1 - p53 functions in adipose tissue metabolism and homeostasis JF - International journal of molecular sciences N2 - As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. A function not directly related to tumor suppression, such as the regulation of metabolism in nontransformed cells, could explain this selective pressure. While this role of p53 in cellular metabolism is gradually emerging, it is imperative to dissect the tissue-and cell-specific actions of p53 and its downstream signaling pathways. In this review, we focus on studies reporting p53's impact on adipocyte development, function, and maintenance, as well as the causes and consequences of altered p53 levels in white and brown adipose tissue (AT) with respect to systemic energy homeostasis. While whole body p53 knockout mice gain less weight and fat mass under a high-fat diet owing to increased energy expenditure, modifying p53 expression specifically in adipocytes yields more refined insights: (1) p53 is a negative regulator of in vitro adipogenesis; (2) p53 levels in white AT are increased in diet-induced and genetic obesity mouse models and in obese humans; (3) functionally, elevated p53 in white AT increases senescence and chronic inflammation, aggravating systemic insulin resistance; (4) p53 is not required for normal development of brown AT; and (5) when p53 is activated in brown AT in mice fed a high-fat diet, it increases brown AT temperature and brown AT marker gene expression, thereby contributing to reduced fat mass accumulation. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways. Hence, despite existence of contradictory findings and a varying density of evidence, several functions of p53 in adipocytes and ATs have been emerging, positioning p53 as an essential regulatory hub in ATs. Future studies need to make use of more sophisticated in vivo model systems and should identify an AT-specific set of p53 target genes and downstream pathways upon different (nutrient) challenges to identify novel therapeutic targets to curb metabolic diseases KW - p53 KW - adipose tissue KW - metabolic syndrome KW - obesity KW - adipogenesis KW - insulin resistance Y1 - 2018 U6 - https://doi.org/10.3390/ijms19092622 SN - 1422-0067 VL - 19 IS - 9 PB - MDPI CY - Basel ER - TY - JOUR A1 - Krstic, Jelena A1 - Galhuber, Markus A1 - Schulz, Tim Julius A1 - Schupp, Michael A1 - Prokesch, Andreas T1 - p53 as a dichotomous regulator of liver disease BT - the dose makes the medicine JF - International journal of molecular sciences N2 - Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues. The transcription factor p53 is well established as a tumor suppressor and has recently been described as a central metabolic player both in physiological and pathological settings. Given that liver is a dynamic tissue with direct exposition to ingested nutrients, hepatic p53, by integrating cellular stress response, metabolism and cell cycle regulation, has emerged as an important regulator of liver homeostasis and dysfunction. The underlying evidence is reviewed herein, with a focus on clinical data and animal studies that highlight a direct influence of p53 activity on different stages of liver diseases. Based on current literature showing that activation of p53 signaling can either attenuate or fuel liver disease, we herein discuss the hypothesis that, while hyper-activation or loss of function can cause disease, moderate induction of hepatic p53 within physiological margins could be beneficial in the prevention and treatment of liver pathologies. Hence, stimuli that lead to a moderate and temporary p53 activation could present new therapeutic approaches through several entry points in the cascade from hepatic steatosis to HCC. KW - p53 KW - liver disease KW - insulin resistance KW - non-alcoholic fatty liver disease KW - non-alcoholic steatohepatitis KW - hepatocellular carcinoma KW - liver regeneration KW - mouse models Y1 - 2018 U6 - https://doi.org/10.3390/ijms19030921 SN - 1422-0067 VL - 19 IS - 3 PB - MDPI CY - Basel ER - TY - GEN A1 - Krstic, Jelena A1 - Galhuber, Markus A1 - Schulz, Tim Julius A1 - Schupp, Michael A1 - Prokesch, Andreas T1 - p53 as a dichotomous regulator of liver disease BT - the dose makes the medicine T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues. The transcription factor p53 is well established as a tumor suppressor and has recently been described as a central metabolic player both in physiological and pathological settings. Given that liver is a dynamic tissue with direct exposition to ingested nutrients, hepatic p53, by integrating cellular stress response, metabolism and cell cycle regulation, has emerged as an important regulator of liver homeostasis and dysfunction. The underlying evidence is reviewed herein, with a focus on clinical data and animal studies that highlight a direct influence of p53 activity on different stages of liver diseases. Based on current literature showing that activation of p53 signaling can either attenuate or fuel liver disease, we herein discuss the hypothesis that, while hyper-activation or loss of function can cause disease, moderate induction of hepatic p53 within physiological margins could be beneficial in the prevention and treatment of liver pathologies. Hence, stimuli that lead to a moderate and temporary p53 activation could present new therapeutic approaches through several entry points in the cascade from hepatic steatosis to HCC. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 963 KW - p53 KW - liver disease KW - insulin resistance KW - non-alcoholic fatty liver disease KW - non-alcoholic steatohepatitis KW - hepatocellular carcinoma KW - liver regeneration KW - mouse models Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-468127 SN - 1866-8372 IS - 963 ER - TY - GEN A1 - Krstic, Jelena A1 - Reinisch, Isabel A1 - Schupp, Michael A1 - Schulz, Tim Julius A1 - Prokesch, Andreas T1 - p53 functions in adipose tissue metabolism and homeostasis T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. A function not directly related to tumor suppression, such as the regulation of metabolism in nontransformed cells, could explain this selective pressure. While this role of p53 in cellular metabolism is gradually emerging, it is imperative to dissect the tissue-and cell-specific actions of p53 and its downstream signaling pathways. In this review, we focus on studies reporting p53's impact on adipocyte development, function, and maintenance, as well as the causes and consequences of altered p53 levels in white and brown adipose tissue (AT) with respect to systemic energy homeostasis. While whole body p53 knockout mice gain less weight and fat mass under a high-fat diet owing to increased energy expenditure, modifying p53 expression specifically in adipocytes yields more refined insights: (1) p53 is a negative regulator of in vitro adipogenesis; (2) p53 levels in white AT are increased in diet-induced and genetic obesity mouse models and in obese humans; (3) functionally, elevated p53 in white AT increases senescence and chronic inflammation, aggravating systemic insulin resistance; (4) p53 is not required for normal development of brown AT; and (5) when p53 is activated in brown AT in mice fed a high-fat diet, it increases brown AT temperature and brown AT marker gene expression, thereby contributing to reduced fat mass accumulation. In addition, p53 is increasingly being recognized as crucial player in nutrient sensing pathways. Hence, despite existence of contradictory findings and a varying density of evidence, several functions of p53 in adipocytes and ATs have been emerging, positioning p53 as an essential regulatory hub in ATs. Future studies need to make use of more sophisticated in vivo model systems and should identify an AT-specific set of p53 target genes and downstream pathways upon different (nutrient) challenges to identify novel therapeutic targets to curb metabolic diseases. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1047 KW - p53 KW - adipose tissue KW - metabolic syndrome KW - obesity KW - adipogenesis KW - insulin resistance Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-469069 SN - 1866-8372 IS - 1047 ER - TY - JOUR A1 - Henkel, Janin A1 - Coleman, Charles Dominic A1 - Schraplau, Anne A1 - Jöhrens, Korinna A1 - Weber, Daniela A1 - Castro, Jose Pedro A1 - Hugo, Martin A1 - Schulz, Tim Julius A1 - Krämer, Stephanie A1 - Schürmann, Annette A1 - Püschel, Gerhard Paul T1 - Induction of Steatohepatitis (NASH) with Insulin Resistance in Wild-type B6 Mice by a Western-type Diet Containing Soybean Oil and Cholesterol JF - Molecular medicine N2 - Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g., high-fat diets) or overweight and insulin resistance (e.g., methionine-choline-deficient diets), or they are based on monogenetic defects (e.g., ob/ob mice). In the current study, a Western-type diet containing soybean oil with high n-6-PUFA and 0.75% cholesterol (SOD + Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice, which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast, a soybean oil-containing Western-type diet without cholesterol (SOD) induced only mild steatosis but not hepatic inflammation, fibrosis, weight gain or insulin resistance. Another high-fat diet, mainly consisting of lard and supplemented with fructose in drinking water (LAD + Fru), resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD + Cho, but livers were devoid of inflammation and fibrosis. Although both LAD + Fru-and SOD + Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD + Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. In summary, dietary cholesterol in the SOD + Cho diet may trigger hepatic inflammation and fibrosis. SOD + Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH. KW - Nonalcoholic Steatohepatitis (NASH) KW - Typical Western Diet KW - Nonalcoholic Fatty Liver Disease (NAFLD) KW - Dietary Cholesterol KW - Kupffer Cells Y1 - 2017 U6 - https://doi.org/10.2119/molmed.2016.00203 SN - 1076-1551 SN - 1528-3658 VL - 23 SP - 70 EP - 82 PB - Feinstein Inst. for Medical Research CY - Manhasset ER - TY - JOUR A1 - Schulz, Tim Julius A1 - Thierbach, Renè A1 - Voigt, Anja A1 - Drewes, Gunnar A1 - Mietzner, Brun A1 - Steinberg, Pablo A1 - Pfeiffer, Andreas F. H. A1 - Ristow, Michael T1 - Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth : Otto Warburg revisited N2 - More than 80 years ago Otto Warburg suggested that cancer might be caused by a decrease in mitochondrial energy metabolism paralleled by an increase in glycolytic flux. In later years, it was shown that cancer cells exhibit multiple alterations in mitochondrial content, structure, function, and activity. We have stably overexpressed the Friedreich ataxia-associated protein frataxin in several colon cancer cell lines. These cells have increased oxidative metabolism, as shown by concurrent increases in aconitase activity, mitochondrial membrane potential, cellular respiration, and ATP content. Consistent with Warburg's hypothesis, we found that frataxin-overexpressing cells also have decreased growth rates and increased population doubling times, show inhibited colony formation capacity in soft agar assays, and exhibit a reduced capacity for tumor formation when injected into nude mice. Furthermore, overexpression of frataxin leads to an increased phosphorylation of the tumor suppressor p38 mitogen-activated protein kinase, as well as decreased phosphorylation of extracellular signal-regulated kinase. Taken together, these results support the view that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals Y1 - 2006 UR - http://www.jbc.org/content/281/2/977.full.pdf+html U6 - https://doi.org/10.1074/jbc.M511064200 ER - TY - JOUR A1 - Thierbach, René A1 - Drewes, Gunnar A1 - Fusser, Markus A1 - Voigt, Anja A1 - Kuhlow, Doreen A1 - Blume, Urte A1 - Schulz, Tim Julius A1 - Reiche, Carina A1 - Glatt, Hansruedi A1 - Epe, Bernd A1 - Steinberg, Pablo A1 - Ristow, Michael T1 - The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals N2 - DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron-sulfur clusters). The nuclear-encoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte- specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA 104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation. Y1 - 2010 UR - http://www.biochemj.org/bj/toc.htm U6 - https://doi.org/10.1042/Bj20101116 SN - 0264-6021 ER - TY - JOUR A1 - Thierbach, Renè A1 - Schulz, Tim Julius A1 - Isken, Frank A1 - Voigt, Aanja A1 - Mietzner, Brun A1 - Drewes, Gunnar A1 - von Kleist-Retzow, Jürgen-Christoph A1 - Wiesner, Rudolf J. A1 - Magnuson, Mark A. A1 - Puccio, Helene A1 - Pfeiffer, Andreas F. H. A1 - Steinberg, Pablo A1 - Ristow, Michael T1 - Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice N2 - We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation. These animals have a reduced life span and develop multiple hepatic tumors. Livers also show increased oxidative stress, impaired respiration and reduced ATP levels paralleled by reduced activity of iron-sulfur cluster (Fe/S) containing proteins (ISP), which all leads to increased hepatocyte turnover by promoting both apoptosis and proliferation. Accordingly, phosphorylation of the stress-inducible p38 MAP kinase was found to be specifically impaired following disruption of frataxin. Taken together, these findings indicate that frataxin may act as a mitochondrial tumor suppressor protein in mammals Y1 - 2005 ER - TY - JOUR A1 - Thierbach, Rene A1 - Schulz, Tim Julius A1 - Voigt, Aanja A1 - Drewes, Gunnar A1 - Isken, F. A1 - Pfeiffer, Andreas F. H. A1 - Ristow, Michael A1 - Steinberg, Pablo T1 - Targeted disruption of frataxin in hepatocytes causes spontaneous neoplasia accompanied by increased ROS formation Y1 - 2004 SN - 0028-1298 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 - Aga-Barfknecht, Heja A1 - Soultoukis, George A. A1 - Stadion, Mandy A1 - Garcia-Carrizo, Francisco A1 - Jähnert, Markus A1 - Gottmann, Pascal A1 - Vogel, Heike A1 - Schulz, Tim Julius A1 - Schürmann, Annette T1 - Distinct adipogenic and fibrogenic differentiation capacities of mesenchymal stromal cells from pancreas and white adipose tissue JF - International journal of molecular sciences N2 - Pancreatic steatosis associates with beta-cell failure and may participate in the development of type-2-diabetes. Our previous studies have shown that diabetes-susceptible mice accumulate more adipocytes in the pancreas than diabetes-resistant mice. In addition, we have demonstrated that the co-culture of pancreatic islets and adipocytes affect insulin secretion. The aim of this current study was to elucidate if and to what extent pancreas-resident mesenchymal stromal cells (MSCs) with adipogenic progenitor potential differ from the corresponding stromal-type cells of the inguinal white adipose tissue (iWAT). miRNA (miRNome) and mRNA expression (transcriptome) analyses of MSCs isolated by flow cytometry of both tissues revealed 121 differentially expressed miRNAs and 1227 differentially expressed genes (DEGs). Target prediction analysis estimated 510 DEGs to be regulated by 58 differentially expressed miRNAs. Pathway analyses of DEGs and miRNA target genes showed unique transcriptional and miRNA signatures in pancreas (pMSCs) and iWAT MSCs (iwatMSCs), for instance fibrogenic and adipogenic differentiation, respectively. Accordingly, iwatMSCs revealed a higher adipogenic lineage commitment, whereas pMSCs showed an elevated fibrogenesis. As a low degree of adipogenesis was also observed in pMSCs of diabetes-susceptible mice, we conclude that the development of pancreatic steatosis has to be induced by other factors not related to cell-autonomous transcriptomic changes and miRNA-based signals. KW - MSCs KW - fatty pancreas KW - WAT KW - lineage commitment KW - transcriptomics KW - miRNAs Y1 - 2022 U6 - https://doi.org/10.3390/ijms23042108 SN - 1422-0067 VL - 23 IS - 4 PB - Molecular Diversity Preservation International CY - Basel ER - TY - JOUR A1 - Fayyaz, Susann A1 - Japtok, Lukasz A1 - Schumacher, Fabian A1 - Wigger, Dominik A1 - Schulz, Tim Julius A1 - Haubold, Kathrin A1 - Gulbins, Erich A1 - Völler, Heinz A1 - Kleuser, Burkhard T1 - Lysophosphatidic acid inhibits insulin signaling in primary rat hepatocytes via the LPA(3) receptor subtype and is increased in obesity JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Background/Aims: Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6). Methods: The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Results: Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25). Conclusion: LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity. KW - Lysophosphatidic acid KW - Insulin signaling KW - Adipose tissue KW - Autotaxin KW - Hepatic insulin resistance KW - LPA(3) receptor subtype Y1 - 2017 U6 - https://doi.org/10.1159/000480470 SN - 1015-8987 SN - 1421-9778 VL - 43 SP - 445 EP - 456 PB - Karger CY - Basel ER - TY - JOUR A1 - Gohlke, Sabrina A1 - Zagoriy, Vyacheslav A1 - Inostroza, Alvaro Cuadros A1 - Meret, Michael A1 - Mancini, Carola A1 - Japtok, Lukasz A1 - Schumacher, Fabian A1 - Kuhlow, Doreen A1 - Graja, Antonia A1 - Stephanowitz, Heike A1 - Jähnert, Markus A1 - Krause, Eberhard A1 - Wernitz, Andreas A1 - Petzke, Klaus-Juergen A1 - Schürmann, Annette A1 - Kleuser, Burkhard A1 - Schulz, Tim Julius T1 - Identification of functional lipid metabolism biomarkers of brown adipose tissue aging JF - Molecular Metabolism N2 - Objective: Aging is accompanied by loss of brown adipocytes and a decline in their thermogenic potential, which may exacerbate the development of adiposity and other metabolic disorders. Presently, only limited evidence exists describing the molecular alterations leading to impaired brown adipogenesis with aging and the contribution of these processes to changes of systemic energy metabolism. Methods: Samples of young and aged murine brown and white adipose tissue were used to compare age-related changes of brown adipogenic gene expression and thermogenesis-related lipid mobilization. To identify potential markers of brown adipose tissue aging, non-targeted proteomic and metabolomic as well as targeted lipid analyses were conducted on young and aged tissue samples. Subsequently, the effects of several candidate lipid classes on brown adipocyte function were examined. Results: Corroborating previous reports of reduced expression of uncoupling protein-1, we observe impaired signaling required for lipid mobilization in aged brown fat after adrenergic stimulation. Omics analyses additionally confirm the age-related impairment of lipid homeostasis and reveal the accumulation of specific lipid classes, including certain sphingolipids, ceramides, and dolichols in aged brown fat. While ceramides as well as enzymes of dolichol metabolism inhibit brown adipogenesis, inhibition of sphingosine 1-phosphate receptor 2 induces brown adipocyte differentiation. Conclusions: Our functional analyses show that changes in specific lipid species, as observed during aging, may contribute to reduced thermogenic potential. They thus uncover potential biomarkers of aging as well as molecular mechanisms that could contribute to the degradation of brown adipocytes, thereby providing potential treatment strategies of age-related metabolic conditions. KW - Brown adipose tissue KW - Aging KW - Ceramides KW - Sphingolipids KW - Dolichol lipids Y1 - 2019 U6 - https://doi.org/10.1016/j.molmet.2019.03.011 SN - 2212-8778 VL - 24 SP - 1 EP - 17 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - McNulty, Margaret A. A1 - Goupil, Brad A. A1 - Albarado, Diana C. A1 - Castaño-Martinez, Teresa A1 - Ambrosi, Thomas H. A1 - Puh, Spela A1 - Schulz, Tim Julius A1 - Schürmann, Annette A1 - Morrison, Christopher D. A1 - Laeger, Thomas T1 - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions JF - Bone Reports N2 - Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone. Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass. Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture. Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21. KW - dietary restriction KW - protein restriction KW - FGF21 KW - GCN2 KW - microcomputed tomography Y1 - 2020 U6 - https://doi.org/10.1016/j.bonr.2019.100241 SN - 2352-1872 VL - 12 SP - 1 EP - 10 PB - Elsevier CY - Amsterdam ER - TY - GEN A1 - McNulty, Margaret A. A1 - Goupil, Brad A. A1 - Albarado, Diana C. A1 - Castaño-Martinez, Teresa A1 - Ambrosi, Thomas H. A1 - Puh, Spela A1 - Schulz, Tim Julius A1 - Schürmann, Annette A1 - Morrison, Christopher D. A1 - Laeger, Thomas T1 - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone. Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass. Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture. Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1406 KW - dietary restriction KW - protein restriction KW - FGF21 KW - GCN2 KW - microcomputed tomography Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516297 SN - 1866-8372 ER - TY - BOOK A1 - Rana, Kaushik A1 - Mohapatra, Durga Prasad A1 - Sidorova, Julia A1 - Lundberg, Lars A1 - Sköld, Lars A1 - Lopes Grim, Luís Fernando A1 - Sampaio Gradvohl, André Leon A1 - Cremerius, Jonas A1 - Siegert, Simon A1 - Weltzien, Anton von A1 - Baldi, Annika A1 - Klessascheck, Finn A1 - Kalancha, Svitlana A1 - Lichtenstein, Tom A1 - Shaabani, Nuhad A1 - Meinel, Christoph A1 - Friedrich, Tobias A1 - Lenzner, Pascal A1 - Schumann, David A1 - Wiese, Ingmar A1 - Sarna, Nicole A1 - Wiese, Lena A1 - Tashkandi, Araek Sami A1 - van der Walt, Estée A1 - Eloff, Jan H. P. A1 - Schmidt, Christopher A1 - Hügle, Johannes A1 - Horschig, Siegfried A1 - Uflacker, Matthias A1 - Najafi, Pejman A1 - Sapegin, Andrey A1 - Cheng, Feng A1 - Stojanovic, Dragan A1 - Stojnev Ilić, Aleksandra A1 - Djordjevic, Igor A1 - Stojanovic, Natalija A1 - Predic, Bratislav A1 - González-Jiménez, Mario A1 - de Lara, Juan A1 - Mischkewitz, Sven A1 - Kainz, Bernhard A1 - van Hoorn, André A1 - Ferme, Vincenzo A1 - Schulz, Henning A1 - Knigge, Marlene A1 - Hecht, Sonja A1 - Prifti, Loina A1 - Krcmar, Helmut A1 - Fabian, Benjamin A1 - Ermakova, Tatiana A1 - Kelkel, Stefan A1 - Baumann, Annika A1 - Morgenstern, Laura A1 - Plauth, Max A1 - Eberhard, Felix A1 - Wolff, Felix A1 - Polze, Andreas A1 - Cech, Tim A1 - Danz, Noel A1 - Noack, Nele Sina A1 - Pirl, Lukas A1 - Beilharz, Jossekin Jakob A1 - De Oliveira, Roberto C. L. A1 - Soares, Fábio Mendes A1 - Juiz, Carlos A1 - Bermejo, Belen A1 - Mühle, Alexander A1 - Grüner, Andreas A1 - Saxena, Vageesh A1 - Gayvoronskaya, Tatiana A1 - Weyand, Christopher A1 - Krause, Mirko A1 - Frank, Markus A1 - Bischoff, Sebastian A1 - Behrens, Freya A1 - Rückin, Julius A1 - Ziegler, Adrian A1 - Vogel, Thomas A1 - Tran, Chinh A1 - Moser, Irene A1 - Grunske, Lars A1 - Szárnyas, Gábor A1 - Marton, József A1 - Maginecz, János A1 - Varró, Dániel A1 - Antal, János Benjamin ED - Meinel, Christoph ED - Polze, Andreas ED - Beins, Karsten ED - Strotmann, Rolf ED - Seibold, Ulrich ED - Rödszus, Kurt ED - Müller, Jürgen T1 - HPI Future SOC Lab – Proceedings 2018 N2 - The “HPI Future SOC Lab” is a cooperation of the Hasso Plattner Institute (HPI) and industry partners. Its mission is to enable and promote exchange and interaction between the research community and the industry partners. The HPI Future SOC Lab provides researchers with free of charge access to a complete infrastructure of state of the art hard and software. This infrastructure includes components, which might be too expensive for an ordinary research environment, such as servers with up to 64 cores and 2 TB main memory. The offerings address researchers particularly from but not limited to the areas of computer science and business information systems. Main areas of research include cloud computing, parallelization, and In-Memory technologies. This technical report presents results of research projects executed in 2018. Selected projects have presented their results on April 17th and November 14th 2017 at the Future SOC Lab Day events. N2 - Das Future SOC Lab am HPI ist eine Kooperation des Hasso-Plattner-Instituts mit verschiedenen Industriepartnern. Seine Aufgabe ist die Ermöglichung und Förderung des Austausches zwischen Forschungsgemeinschaft und Industrie. Am Lab wird interessierten Wissenschaftler:innen eine Infrastruktur von neuester Hard- und Software kostenfrei für Forschungszwecke zur Verfügung gestellt. Dazu zählen Systeme, die im normalen Hochschulbereich in der Regel nicht zu finanzieren wären, bspw. Server mit bis zu 64 Cores und 2 TB Hauptspeicher. Diese Angebote richten sich insbesondere an Wissenschaftler:innen in den Gebieten Informatik und Wirtschaftsinformatik. Einige der Schwerpunkte sind Cloud Computing, Parallelisierung und In-Memory Technologien. In diesem Technischen Bericht werden die Ergebnisse der Forschungsprojekte des Jahres 2018 vorgestellt. Ausgewählte Projekte stellten ihre Ergebnisse am 17. April und 14. November 2018 im Rahmen des Future SOC Lab Tags vor. T3 - Technische Berichte des Hasso-Plattner-Instituts für Digital Engineering an der Universität Potsdam - 151 KW - Future SOC Lab KW - research projects KW - multicore architectures KW - in-memory technology KW - cloud computing KW - machine learning KW - artifical intelligence KW - Future SOC Lab KW - Forschungsprojekte KW - Multicore Architekturen KW - In-Memory Technologie KW - Cloud Computing KW - maschinelles Lernen KW - künstliche Intelligenz Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-563712 SN - 978-3-86956-547-7 SN - 1613-5652 SN - 2191-1665 IS - 151 PB - Universitätsverlag Potsdam CY - Potsdam ER -