@phdthesis{Polemiti2022,
  author    = {Polemiti, Elli},
  title     = {Identifying risk of microvascular and macrovascular complications of type 2 diabetes},
  doi       = {10.25932/publishup-57103},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-571038},
  school      = {Universit{\"a}t Potsdam},
  pages     = {xii, 292},
  year      = {2022},
  abstract  = {Diabetes is hallmarked by high blood glucose levels, which cause progressive generalised vascular damage, leading to microvascular and macrovascular complications. Diabetes-related complications cause severe and prolonged morbidity and are a major cause of mortality among people with diabetes. Despite increasing attention to risk factors of type 2 diabetes, existing evidence is scarce or inconclusive regarding vascular complications and research investigating both micro- and macrovascular complications is lacking. This thesis aims to contribute to current knowledge by identifying risk factors - mainly related to lifestyle - of vascular complications, addressing methodological limitations of previous literature and providing comparative data between micro- and macrovascular complications. To address this overall aim, three specific objectives were set. The first was to investigate the effects of diabetes complication burden and lifestyle-related risk factors on the incidence of (further) complications. Studies suggest that diabetes complications are interrelated. However, they have been studied mainly independently of individuals' complication burden. A five-state time-to-event model was constructed to examine the longitudinal patterns of micro- (kidney disease, neuropathy and retinopathy) and macrovascular complications (myocardial infarction and stroke) and their association with the occurrence of subsequent complications. Applying the same model, the effect of modifiable lifestyle factors, assessed alone and in combination with complication load, on the incidence of diabetes complications was studied. The selected lifestyle factors were body mass index (BMI), waist circumference, smoking status, physical activity, and intake of coffee, red meat, whole grains, and alcohol. Analyses were conducted in a cohort of 1199 participants with incident type 2 diabetes from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam, who were free of vascular complications at diabetes diagnosis. During a median follow-up time of 11.6 years, 96 cases of macrovascular complications (myocardial infarction and stroke) and 383 microvascular complications (kidney disease, neuropathy and retinopathy) were identified. In multivariable-adjusted models, the occurrence of a microvascular complication was associated with a higher incidence of further micro- (Hazard ratio [HR] 1.90; 95\% Confidence interval [CI] 0.90, 3.98) and macrovascular complications (HR 4.72; 95\% CI 1.25, 17.68), compared with persons without a complication burden. In addition, participants who developed a macrovascular event had a twofold higher risk of future microvascular complications (HR 2.26; 95\% CI 1.05, 4.86). The models were adjusted for age, sex, state duration, education, lifestyle, glucose-lowering medication, and pre-existing conditions of hypertension and dyslipidaemia. Smoking was positively associated with macrovascular disease, while an inverse association was observed with higher coffee intake. Whole grain and alcohol intake were inversely associated with microvascular complications, and a U-shaped association was observed for red meat intake. BMI and waist circumference were positively associated with microvascular events. The associations between lifestyle factors and incidence of complications were not modified by concurrent complication burden, except for red meat intake and smoking status, where the associations were attenuated among individuals with a previous complication. The second objective was to perform an in-depth investigation of the association between BMI and BMI change and risk of micro- and macrovascular complications. There is an ongoing debate on the association between obesity and risk of macrovascular and microvascular outcomes in type 2 diabetes, with studies suggesting a protective effect among people with overweight or obesity. These findings, however, might be limited due to suboptimal control for smoking, pre-existing chronic disease, or short-follow-up. After additional exclusion of persons with cancer history at diabetes onset, the associations between pre-diagnosis BMI and relative annual change between pre- and post-diagnosis BMI and incidence of complications were evaluated in multivariable-adjusted Cox models. The analyses were adjusted for age, sex, education, smoking status and duration, physical activity, alcohol consumption, adherence to the Mediterranean diet, and family history of diabetes and cardiovascular disease (CVD). Among 1083 EPIC-Potsdam participants, 85 macrovascular and 347 microvascular complications were identified during a median follow-up period of 10.8 years. Higher pre-diagnosis BMI was associated with an increased risk of total microvascular complications (HR per 5 kg/m2 1.21; 95\% CI 1.07, 1.36), kidney disease (HR 1.39; 95\% CI 1.21, 1.60) and neuropathy (HR 1.12; 95\% CI 0.96, 1.31); but no association was observed for macrovascular complications (HR 1.05; 95\% CI 0.81, 1.36). Effect modification was not evident by sex, smoking status, or age groups. In analyses according to BMI change categories, BMI loss of more than 1\% indicated a decreased risk of total microvascular complications (HR 0.62; 95\% CI 0.47, 0.80), kidney disease (HR 0.57; 95\% CI 0.40, 0.81) and neuropathy (HR 0.73; 95\% CI 0.52, 1.03), compared with participants with a stable BMI. No clear association was observed for macrovascular complications (HR 1.04; 95\% CI 0.62, 1.74). The impact of BMI gain on diabetes-related vascular disease was less evident. Associations were consistent across strata of age, sex, pre-diagnosis BMI, or medication but appeared stronger among never-smokers than current or former smokers. The last objective was to evaluate whether individuals with a high-risk profile for diabetes and cardiovascular disease (CVD) also have a greater risk of complications. Within the EPIC-Potsdam study, two accurate prognostic tools were developed, the German Diabetes Risk Score (GDRS) and the CVD Risk Score (CVDRS), which predict the 5-year type 2 diabetes risk and 10-year CVD risk, respectively. Both scores provide a non-clinical and clinical version. Components of the risk scores include age, sex, waist circumference, prevalence of hypertension, family history of diabetes or CVD, lifestyle factors, and clinical factors (only in clinical versions). The association of the risk scores with diabetes complications and their discriminatory performance for complications were assessed. In crude Cox models, both versions of GDRS and CVDRS were positively associated with macrovascular complications and total microvascular complications, kidney disease and neuropathy. Higher GDRS was also associated with an elevated risk of retinopathy. The discrimination of the scores (clinical and non-clinical) was poor for all complications, with the C-index ranging from 0.58 to 0.66 for macrovascular complications and from 0.60 to 0.62 for microvascular complications. In conclusion, this work illustrates that the risk of complication development among individuals with type 2 diabetes is related to the existing complication load, and attention should be given to regular monitoring for future complications. It underlines the importance of weight management and adherence to healthy lifestyle behaviours, including high intake of whole grains, moderation in red meat and alcohol consumption and avoidance of smoking to prevent major diabetes-associated complications, regardless of complication burden. Risk scores predictive for type 2 diabetes and CVD were related to elevated risks of complications. By optimising several lifestyle and clinical factors, the risk score can be improved and may assist in lowering complication risk.},
  language  = {en}
}
@misc{PueschelKlauderHenkelOberlaender,
  author    = {P{\"u}schel, Gerhard Paul and Klauder, Julia and Henkel-Oberl{\"a}nder, Janin},
  title     = {Macrophages, Low-Grade Inflammation, Insulin Resistance and Hyperinsulinemia: A Mutual Ambiguous Relationship in the Development of Metabolic Diseases},
  series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {1279},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-57010},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-570106},
  pages     = {1 -- 30},
  abstract  = {Metabolic derangement with poor glycemic control accompanying overweight and obesity is associated with chronic low-grade inflammation and hyperinsulinemia. Macrophages, which present a very heterogeneous population of cells, play a key role in the maintenance of normal tissue homeostasis, but functional alterations in the resident macrophage pool as well as newly recruited monocyte-derived macrophages are important drivers in the development of low-grade inflammation. While metabolic dysfunction, insulin resistance and tissue damage may trigger or advance pro-inflammatory responses in macrophages, the inflammation itself contributes to the development of insulin resistance and the resulting hyperinsulinemia. Macrophages express insulin receptors whose downstream signaling networks share a number of knots with the signaling pathways of pattern recognition and cytokine receptors, which shape macrophage polarity. The shared knots allow insulin to enhance or attenuate both pro-inflammatory and anti-inflammatory macrophage responses. This supposedly physiological function may be impaired by hyperinsulinemia or insulin resistance in macrophages. This review discusses the mutual ambiguous relationship of low-grade inflammation, insulin resistance, hyperinsulinemia and the insulin-dependent modulation of macrophage activity with a focus on adipose tissue and liver.},
  language  = {en}
}
@article{PueschelKlauderHenkelOberlaender2022,
  author    = {P{\"u}schel, Gerhard and Klauder, Julia and Henkel-Oberl{\"a}nder, Janin},
  title     = {Macrophages, low-grade inflammation, insulin resistance and hyperinsulinemia},
  series = {Journal of Clinical Medicine : open access journal},
  volume    = {11},
  journal   = {Journal of Clinical Medicine : open access journal},
  number    = {15},
  publisher = {MDPI},
  address   = {Basel, Schweiz},
  issn      = {2077-0383},
  doi       = {10.3390/jcm11154358},
  pages     = {1 -- 30},
  year      = {2022},
  abstract  = {Metabolic derangement with poor glycemic control accompanying overweight and obesity is associated with chronic low-grade inflammation and hyperinsulinemia. Macrophages, which present a very heterogeneous population of cells, play a key role in the maintenance of normal tissue homeostasis, but functional alterations in the resident macrophage pool as well as newly recruited monocyte-derived macrophages are important drivers in the development of low-grade inflammation. While metabolic dysfunction, insulin resistance and tissue damage may trigger or advance pro-inflammatory responses in macrophages, the inflammation itself contributes to the development of insulin resistance and the resulting hyperinsulinemia. Macrophages express insulin receptors whose downstream signaling networks share a number of knots with the signaling pathways of pattern recognition and cytokine receptors, which shape macrophage polarity. The shared knots allow insulin to enhance or attenuate both pro-inflammatory and anti-inflammatory macrophage responses. This supposedly physiological function may be impaired by hyperinsulinemia or insulin resistance in macrophages. This review discusses the mutual ambiguous relationship of low-grade inflammation, insulin resistance, hyperinsulinemia and the insulin-dependent modulation of macrophage activity with a focus on adipose tissue and liver.},
  language  = {en}
}
@phdthesis{Bishop2022,
  author    = {Bishop, Christopher Allen},
  title     = {Influence of dairy intake on odd-chain fatty acids and energy metabolism},
  doi       = {10.25932/publishup-56154},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-561541},
  school      = {Universit{\"a}t Potsdam},
  pages     = {xii, 104, xv},
  year      = {2022},
  abstract  = {As of late, epidemiological studies have highlighted a strong association of dairy intake with lower disease risk, and similarly with an increased amount of odd-chain fatty acids (OCFA). While the OCFA also demonstrate inverse associations with disease incidence, the direct dietary sources and mode of action of the OCFA remain poorly understood. The overall aim of this thesis was to determine the impact of two main fractions of dairy, milk fat and milk protein, on OCFA levels and their influence on health outcomes under high-fat (HF) diet conditions. Both fractions represent viable sources of OCFA, as milk fats contain a significant amount of OCFA and milk proteins are high in branched chain amino acids (BCAA), namely valine (Val) and isoleucine (Ile), which can produce propionyl-CoA (Pr-CoA), a precursor for endogenous OCFA synthesis, while leucine (Leu) does not. Additionally, this project sought to clarify the specific metabolic effects of the OCFA heptadecanoic acid (C17:0). Both short-term and long-term feeding studies were performed using male C57BL/6JRj mice fed HF diets supplemented with milk fat or C17:0, as well as milk protein or individual BCAA (Val; Leu) to determine their influences on OCFA and metabolic health. Short-term feeding revealed that both milk fractions induce OCFA in vivo, and the increases elicited by milk protein could be, in part, explained by Val intake. In vitro studies using primary hepatocytes further showed an induction of OCFA after Val treatment via de novo lipogenesis and increased α-oxidation. In the long-term studies, both milk fat and milk protein increased hepatic and circulating OCFA levels; however, only milk protein elicited protective effects on adiposity and hepatic fat accumulation—likely mediated by the anti-obesogenic effects of an increased Leu intake. In contrast, Val feeding did not increase OCFA levels nor improve obesity, but rather resulted in glucotoxicity-induced insulin resistance in skeletal muscle mediated by its metabolite 3-hydroxyisobutyrate (3-HIB). Finally, while OCFA levels correlated with improved health outcomes, C17:0 produced negligible effects in preventing HF-diet induced health impairments. The results presented herein demonstrate that the beneficial health outcomes associated with dairy intake are likely mediated through the effects of milk protein, while OCFA levels are likely a mere association and do not play a significant causal role in metabolic health under HF conditions. Furthermore, the highly divergent metabolic effects of the two BCAA, Leu and Val, unraveled herein highlight the importance of protein quality.},
  language  = {en}
}
@misc{HauffeRathAgyapongetal.2022,
  author    = {Hauffe, Robert and Rath, Michaela and Agyapong, Wilson and Jonas, Wenke and Vogel, Heike and Schulz, Tim Julius and Schwarz, Maria and Kipp, Anna Patricia and Bl{\"u}her, Matthias and Kleinridders, Andr{\´e}},
  title     = {Obesity Hinders the Protective Effect of Selenite Supplementation on Insulin Signaling},
  series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  publisher = {Universit{\"a}tsverlag Potsdam},
  address   = {Potsdam},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-56170},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-561709},
  pages     = {1 -- 16},
  year      = {2022},
  abstract  = {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.},
  language  = {en}
}
@article{HauffeRathAgyapongetal.2022,
  author    = {Hauffe, Robert and Rath, Michaela and Agyapong, Wilson and Jonas, Wenke and Vogel, Heike and Schulz, Tim Julius and Schwarz, Maria and Kipp, Anna Patricia and Bl{\"u}her, Matthias and Kleinridders, Andr{\´e}},
  title     = {Obesity Hinders the Protective Effect of Selenite Supplementation on Insulin Signaling},
  series = {Antioxidants},
  volume    = {11},
  journal   = {Antioxidants},
  edition   = {5},
  publisher = {MDPI},
  address   = {Basel, Schweiz},
  issn      = {2076-3921},
  doi       = {10.3390/antiox11050862},
  pages     = {1 -- 16},
  year      = {2022},
  abstract  = {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.},
  language  = {en}
}
@phdthesis{Schell2022,
  author    = {Schell, Mareike},
  title     = {Investigating the effect of Lactobacillus rhamnosus GG on emotional behavior in diet-induced obese C57BL/6N mice},
  school      = {Universit{\"a}t Potsdam},
  pages     = {XVI, 117},
  year      = {2022},
  abstract  = {The prevalence of depression and anxiety is increased in obese patients compared to healthy humans, which is partially due to a shared pathogenesis, including insulin resistance and inflammation. These factors are also linked to intestinal dysbiosis. Additionally, the chronic consumption of diets rich in saturated fats results in body weight gain, hormonal resistances and unfavorable changes in the microbiome composition. The intake of Lactobacilli has already been shown to improve dysbiosis along with metabolism and mood. Yet, the beneficial role and the underlying mechanism of Lactobacillus rhamnosus GG (LGG) to improve emotional behavior in established diet-induced obese conditions are, so far, unknown. To characterize the role of LGG in diet-induced obesity, female and male C57BL/6N mice were fed a semi-synthetic low-fat diet (LFD, 10 \% kcal from fat) or a conventional high-fat diet (HFD, 45 \% kcal from fat) for initial 6 weeks, which was followed by daily oral gavage of vehicle or 1x10^8 CFU of LGG until the end of the experiment. Mice were subjected to basic metabolic and extensive behavioral phenotyping, with a focus on emotional behavior. Moreover, composition of cecal gut microbiome, metabolomic profile in plasma and cerebrospinal fluid was investigated and followed by molecular analyses. Both HFD-feeding and LGG application resulted in sex-specific differences. While LGG prevented the increase of plasma insulin, adrenal gland weight and hyperactivity in diet-induced obese female mice, there was no regulation of anxiodepressive-like behavior. In contrast, metabolism of male mice did not benefit from LGG application, but strikingly, LGG decreased specifically depressive-like behavior in the Mousetail Suspension Test which was confirmed by the Splash Test characterizing motivation for 'self-care'. The microbiome analysis in male mice revealed that HFD-feeding, but not LGG application, altered cecal microbiome composition, indicating a direct effect of LGG on behavioral regulation. However, in female mice, both HFD-feeding and LGG application resulted in changes of microbiome composition, which presumably affected metabolism. Moreover, as diet-induced obese female mice unexpectedly did not exhibit anxiodepressive-like behavior, follow-up analyses were conducted in male mice. Here, HFD-feeding significantly altered abundance of plasma lipids whereas LGG decreased branched chain amino acids which associated with improved emotional behavior. In nucleus accumbens (NAcc) and VTA/SN, which belong to the dopaminergic system, LGG restored HFD-induced decrease of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, on gene expression level. Lastly, transcriptome analysis in the NAcc identified gene expression of cholecystokinin as a potential mediator of the effect of LGG on HFD-induced emotional alterations. In summary, this thesis revealed the beneficial effects of LGG application on emotional alterations in established diet-induced obesity. Furthermore, both HFD-feeding and LGG treatment exhibited sex-specific effects, resulting in metabolic improvements in female mice while LGG application mitigated depressive-like behavior in obese male mice along with a molecular signature of restored dopamine synthesis and neuropeptide signaling.},
  language  = {en}
}
@misc{KrsticReinischSchuppetal.2018,
  author    = {Krstic, Jelena and Reinisch, Isabel and Schupp, Michael and Schulz, Tim Julius and Prokesch, Andreas},
  title     = {p53 functions in adipose tissue metabolism and homeostasis},
  series = {International journal of molecular sciences},
  volume    = {19},
  journal   = {International journal of molecular sciences},
  number    = {9},
  publisher = {MDPI},
  address   = {Basel},
  issn      = {1422-0067},
  doi       = {10.3390/ijms19092622},
  pages     = {21},
  year      = {2018},
  abstract  = {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},
  language  = {en}
}
@phdthesis{HenkelOberlaender2020,
  author    = {Henkel-Oberl{\"a}nder, Janin},
  title     = {Einfluss von Prostaglandin E2 auf die Entstehung von Insulinresistenz und die Regulation der Entz{\"u}ndungsantwort bei der Di{\"a}t-induzierten nicht-alkoholischen Fettlebererkrankung},
  pages     = {171},
  year      = {2020},
  abstract  = {Weltweit sind fast 40 \% der Bev{\"o}lkerung {\"u}bergewichtig und die Pr{\"a}valenz von Adipositas, Insulinresistenz und den resultierenden Folgeerkrankungen wie dem Metabolischen Syndrom und Typ-2-Diabetes steigt rapide an. Als h{\"a}ufigste Ursachen werden di{\"a}tetisches Fehlverhalten und mangelnde Bewegung angesehen. Die nicht-alkoholische Fettlebererkrankung (NAFLD), deren Hauptcharakteristikum die exzessive Akkumulation von Lipiden in der Leber ist, korreliert mit dem Body Mass Index (BMI). NAFLD wird als hepatische Manifestation des Metabolischen Syndroms angesehen und ist inzwischen die h{\"a}ufigste Ursache f{\"u}r Leberfunktionsst{\"o}rungen. Die Erkrankung umfasst sowohl die benigne hepatische Steatose (Fettleber) als auch die progressive Form der nicht-alkoholischen Steatohepatitis (NASH), bei der die Steatose von Entz{\"u}ndung und Fibrose begleitet ist. Die Ausbildung einer NASH erh{\"o}ht das Risiko, ein hepatozellul{\"a}res Karzinom (HCC) zu entwickeln und kann zu irreversibler Leberzirrhose und terminalem Organversagen f{\"u}hren. Nahrungsbestandteile wie Cholesterol und Fett-reiche Di{\"a}ten werden als m{\"o}gliche Faktoren diskutiert, die den {\"U}bergang einer einfachen Fettleber zur schweren Verlaufsform der Steatohepatitis / NASH beg{\"u}nstigen. Eine Ausdehnung des Fettgewebes wird von Insulinresistenz und einer niedrig-gradigen chronischen Entz{\"u}ndung des Fettgewebes begleitet. Neben Endotoxinen aus dem Darm gelangen Entz{\"u}ndungsmediatoren aus dem Fettgewebe zur Leber. Als Folge werden residente Makrophagen der Leber, die Kupfferzellen, aktiviert, die eine Entz{\"u}ndungsantwort initiieren und weitere pro-inflammatorische Mediatoren freisetzen, zu denen Chemokine, Cytokine und Prostanoide wie Prostaglandin E2 (PGE2) geh{\"o}ren. In dieser Arbeit soll aufgekl{\"a}rt werden, welchen Beitrag PGE2 an der Ausbildung von Insulinresistenz, hepatischer Steatose und Entz{\"u}ndung im Rahmen von Di{\"a}t-induzierter NASH im komplexen Zusammenspiel mit der Regulation der Cytokin-Produktion und anderen Co-Faktoren wie Hyperinsulin{\"a}mie und Hyperlipid{\"a}mie hat. In murinen und humanen Makrophagen-Populationen wurde untersucht, welche Faktoren die Bildung von PGE2 f{\"o}rdern und wie PGE2 die Entz{\"u}ndungsantwort aktivierter Makrophagen reguliert. In prim{\"a}ren Hepatozyten der Ratte sowie in isolierten humanen Hepatozyten und Zelllinien wurde der Einfluss von PGE2 allein und in Kombination mit Cytokinen, deren Bildung durch PGE2 beeinflusst werden kann, auf die Insulin-abh{\"a}ngige Regulation des Glucose- und Lipid-stoffwechsels untersucht. Um den Einfluss von PGE2 im komplexen Zusammenspiel der Zelltypen in der Leber und im Gesamtorganismus zu erfassen, wurden M{\"a}use, in denen die PGE2-Synthese durch die Deletion der mikrosomalen PGE-Synthase 1 (mPGES1) vermindert war, mit einer NASH-induzierenden Di{\"a}t gef{\"u}ttert. In Lebern von Patienten mit NASH oder in M{\"a}usen mit Di{\"a}t-induzierter NASH war die Expression der PGE2-synthetisierenden Enzyme Cyclooxygenase 2 (COX2) und mPGES1 sowie die Bildung von PGE2 im Vergleich zu gesunden Kontrollen gesteigert und korrelierte mit dem Schweregrad der Lebererkrankung. In prim{\"a}ren Makrophagen aus den Spezies Mensch, Maus und Ratte sowie in humanen Makrophagen-Zelllinien war die Bildung pro-inflammatorischer Mediatoren wie Chemokinen, Cytokinen und Prostaglandinen wie PGE2 verst{\"a}rkt, wenn die Zellen mit Endotoxinen wie Lipopolysaccharid (LPS), Fetts{\"a}uren wie Palmitins{\"a}ure, Cholesterol und Cholesterol-Kristallen oder Insulin, das als Folge der kompensatorischen Hyperinsulin{\"a}mie bei Insulinresistenz verst{\"a}rkt freigesetzt wird, inkubiert wurden. Insulin steigerte dabei synergistisch mit LPS oder Palmitins{\"a}ure die Synthese von PGE2 sowie der anderen Entz{\"u}ndungsmediatoren wie Interleukin (IL) 8 und IL-1β. PGE2 reguliert die Entz{\"u}ndungsantwort: Neben der Induktion der eigenen Synthese-Enzyme verst{\"a}rkte PGE2 die Expression der Immunzell-rekrutierenden Chemokine IL-8 und (C-C-Motiv)-Ligand 2 (CCL2) sowie die der pro-inflammatorischen Cytokine IL-1β und IL-6 in Makrophagen und kann so zur Verst{\"a}rkung der Entz{\"u}ndungsreaktion beitragen. Außerdem f{\"o}rderte PGE2 die Bildung von Oncostatin M (OSM) und OSM induzierte in einer positiven R{\"u}ckkopplungsschleife die Expression der PGE2-synthetisierenden Enzyme. Andererseits hemmte PGE2 die basale und LPS-vermittelte Bildung des potenten pro-inflammatorischen Cytokins Tumornekrosefaktor α (TNFα) und kann so die Entz{\"u}ndungsreaktion abschw{\"a}chen. In prim{\"a}ren Hepatozyten der Ratte und humanen Hepatozyten beeintr{\"a}chtigte PGE2 direkt die Insulin-abh{\"a}ngige Aktivierung der Insulinrezeptor-Signalkette zur Steigerung der Glucose-Verwertung, in dem es durch Signalketten, die den verschiedenen PGE2-Rezeptoren nachgeschaltet sind, Kinasen wie ERK1/2 und IKKβ aktivierte und eine inhibierende Serin-Phosphorylierung der Insulinrezeptorsubstrate bewirkte. PGE2 verst{\"a}rkte außerdem die IL-6- oder OSM-vermittelte Insulinresistenz und Steatose in prim{\"a}ren Hepatozyten der Ratte. Die Wirkung von PGE2 im Gesamtorganismus sollte in M{\"a}usen mit Di{\"a}t-induzierter NASH untersucht werden. Die F{\"u}tterung einer Hochfett-Di{\"a}t mit Schmalz als Fettquelle, das vor allem ges{\"a}ttigte Fetts{\"a}uren enth{\"a}lt, verursachte Fettleibigkeit, Insulinresistenz und eine hepatische Steatose in Wildtyp-M{\"a}usen. In Tieren, die eine Hochfett-Di{\"a}t mit Soja{\"o}l als Fettquelle, das vor allem (ω-6)-mehrfach-unges{\"a}ttigte Fetts{\"a}uren (PUFAs) enth{\"a}lt, oder eine Niedrigfett-Di{\"a}t mit Cholesterol erhielten, war lediglich eine hepatische Steatose nachweisbar, jedoch keine verst{\"a}rkte Gewichtszunahme im Vergleich zu Geschwistertieren, die eine Standard-Di{\"a}t bekamen. Im Gegensatz dazu verursachte die F{\"u}tterung einer Hochfett-Di{\"a}t mit PUFA-reichem Soja{\"o}l als Fettquelle in Kombination mit Cholesterol sowohl Fettleibigkeit und Insulinresistenz als auch hepatische Steatose mit Hepatozyten-Hypertrophie, lobul{\"a}rer Entz{\"u}ndung und beginnender Fibrose in Wildtyp-M{\"a}usen. Diese Tiere spiegelten alle klinischen und histologischen Parameter der humanen NASH im Metabolischen Syndrom wider. Nur die Kombination von hohen Mengen unges{\"a}ttigter Fetts{\"a}uren aus Soja{\"o}l und Cholesterol in der Nahrung f{\"u}hrte zu einer exzessiven Akkumulation des Cholesterols und der Bildung von Cholesterol-Kristallen in den Hepatozyten, die zur Sch{\"a}digung der Mitochondrien, schwerem oxidativem Stress und schließlich zum Absterben der Zellen f{\"u}hrten. Als Konsequenz phagozytieren Kupfferzellen die Zelltr{\"u}mmer der Cholesterol-{\"u}berladenen Hepatozyten, werden dadurch aktiviert, setzen Chemokine, Cytokine und PGE2 frei, die die Entz{\"u}ndungsreaktion verst{\"a}rken und die Infiltration von weiteren Immunzellen initiieren k{\"o}nnen und verursachen so eine Progression zur Steatohepatitis (NASH). Die Deletion der mikrosomalen PGE-Synthase 1 (mPGES1), dem induzierbaren Enzym der PGE2-Synthese aus Cyclooxygenase-abh{\"a}ngigen Vorstufen, reduzierte die Di{\"a}t-abh{\"a}ngige Bildung von PGE2 in der Leber. Die F{\"u}tterung der NASH-induzierenden Di{\"a}t verursachte in Wildtyp- und mPGES1-defizienten M{\"a}usen eine {\"a}hnliche Fettleibigkeit und Zunahme der Fettmasse sowie die Ausbildung von hepatischer Steatose mit Entz{\"u}ndung und Fibrose (NASH) im histologischen Bild. In mPGES1-defizienten M{\"a}usen waren jedoch Parameter f{\"u}r die Infiltration von Entz{\"u}ndungszellen und die Di{\"a}t-abh{\"a}ngige Sch{\"a}digung der Leber im Vergleich zu Wildtyp-Tieren erh{\"o}ht, was sich auch in einer st{\"a}rkeren Di{\"a}t-induzierten systemischen Insulinresistenz widerspiegelte. Die Bildung des pro-inflammatorischen und pro-apoptotischen Cytokins TNFα war in mPGES1-defizienten M{\"a}usen durch die Aufhebung der negativen R{\"u}ckkopplungshemmung verst{\"a}rkt, was einen gesteigerten Di{\"a}t-induzierten Zelluntergang gestresster Lipid-{\"u}berladener Hepatozyten und eine nach-geschaltete Entz{\"u}ndungsantwort zur Folge hatte. Zusammenfassend wurde unter den gew{\"a}hlten Versuchsbedingungen in vivo eine anti-inflammatorische Rolle von PGE2 verifiziert, da das Prostanoid vor allem indirekt durch die Hemmung der TNFα-vermittelten Entz{\"u}ndungsreaktion die Sch{\"a}digung der Leber, die Verst{\"a}rkung der Entz{\"u}ndung und die Ausbildung von Insulinresistenz im Rahmen der Di{\"a}t-abh{\"a}ngigen Fettlebererkrankung abschw{\"a}chte.},
  language  = {de}
}
@misc{KrsticReinischSchuppetal.2018,
  author    = {Krstic, Jelena and Reinisch, Isabel and Schupp, Michael and Schulz, Tim Julius and Prokesch, Andreas},
  title     = {p53 functions in adipose tissue metabolism and homeostasis},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {1047},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-46906},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-469069},
  pages     = {21},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}