TY - JOUR A1 - Göldel, Julia M. A1 - Kamrath, Clemens A1 - Minden, Kirsten A1 - Wiegand, Susanna A1 - Lanzinger, Stefanie A1 - Sengler, Claudia A1 - Weihrauch-Blüher, Susann A1 - Holl, Reinhard W. A1 - Tittel, Sascha René A1 - Warschburger, Petra T1 - Access to Healthcare for Children and Adolescents with a Chronic Health Condition during the COVID-19 Pandemic: First Results from the KICK-COVID Study in Germany JF - Children N2 - This study examines the access to healthcare for children and adolescents with three common chronic diseases (type-1 diabetes (T1D), obesity, or juvenile idiopathic arthritis (JIA)) within the 4th (Delta), 5th (Omicron), and beginning of the 6th (Omicron) wave (June 2021 until July 2022) of the COVID-19 pandemic in Germany in a cross-sectional study using three national patient registries. A paper-and-pencil questionnaire was given to parents of pediatric patients (<21 years) during the routine check-ups. The questionnaire contains self-constructed items assessing the frequency of healthcare appointments and cancellations, remote healthcare, and satisfaction with healthcare. In total, 905 parents participated in the T1D-sample, 175 in the obesity-sample, and 786 in the JIA-sample. In general, satisfaction with healthcare (scale: 0–10; 10 reflecting the highest satisfaction) was quite high (median values: T1D 10, JIA 10, obesity 8.5). The proportion of children and adolescents with canceled appointments was relatively small (T1D 14.1%, JIA 11.1%, obesity 20%), with a median of 1 missed appointment, respectively. Only a few parents (T1D 8.6%; obesity 13.1%; JIA 5%) reported obstacles regarding health services during the pandemic. To conclude, it seems that access to healthcare was largely preserved for children and adolescents with chronic health conditions during the COVID-19 pandemic in Germany. KW - chronic health condition KW - children and adolescents KW - health care KW - COVID-19 pandemic KW - diabetes KW - rheumatic diseases KW - obesity Y1 - 2022 U6 - https://doi.org/10.3390/children10010010 SN - 2227-9067 VL - 10 SP - 1 EP - 11 PB - MDPI CY - Basel, Schweiz ET - 1 ER - TY - JOUR A1 - Püschel, Gerhard A1 - Klauder, Julia A1 - Henkel-Oberländer, Janin T1 - Macrophages, low-grade inflammation, insulin resistance and hyperinsulinemia BT - A mutual ambiguous relationship in the development of metabolic diseases JF - Journal of Clinical Medicine : open access journal N2 - 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. KW - NAFLD/MAFLD KW - type 2 diabetes KW - obesity KW - vicious cycle KW - TLR signaling KW - M1/M2 differentiation KW - Akt pathway Y1 - 2022 U6 - https://doi.org/10.3390/jcm11154358 SN - 2077-0383 VL - 11 IS - 15 SP - 1 EP - 30 PB - MDPI CY - Basel, Schweiz 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 - THES A1 - Schell, Mareike T1 - Investigating the effect of Lactobacillus rhamnosus GG on emotional behavior in diet-induced obese C57BL/6N mice T1 - Untersuchung der Wirkung von Lactobacillus rhamnosus GG bei Störungen des emotionalen Verhaltens in einem Mausmodell Diät-induzierter Adipositas N2 - 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. N2 - n adipösen Patienten liegt eine erhöhte Prävalenz von Depressionen und Angsterkrankungen vor. Dies liegt unter anderem an einer gemeinsamen Pathogenese, der eine Insulinresistenz sowie ein chronischer Entzündungszustand zugrunde liegen. Diese Faktoren sind mit einer intestinalen Dysbiose assoziiert, die auch durch eine Fehlernährung, beispielsweise mit einer fettreichen Diät, hervorgerufen werden kann. Es konnte bereits gezeigt werden, dass die Aufnahme von Laktobazillen nicht nur eine Dysbiose und den Stoffwechsel verbessert, sondern sich auch positiv auf das Gemüt auswirken kann. Ob jedoch Lactobacillus rhamnosus GG in der Lage ist, in einem Zustand der etablierten ernährungsbedingten Fettleibigkeit das emotionale Verhalten zu verbessern und welche Mechanismen zugrunde liegen, ist noch ungeklärt. Um die Rolle von LGG bei ernährungsbedingter Fettleibigkeit zu charakterisieren, wurden weibliche und männliche C57BL/6N Mäuse mit einer semi-synthetischen Niedrigfettdiät (LFD, 10 % kcal aus Fett) oder einer konventionellen Hochfettdiät (HFD, 45 % kcal aus Fett) für die ersten 6 Wochen gefüttert, um den Zustand einer Adipositas zu etablieren. Anschließend haben die Mäuse eine tägliche perorale Applikation eines Vehikels oder 1x10^8 KBE LGG bis zum Versuchsende erhalten. Die Mäuse wurden einer allgemeinen metabolischen Charakterisierung und einer umfassenden Verhaltensphänotypisierung unterzogen, die Aufschlüsse über das emotionale Verhalten liefern sollen. Darüber hinaus wurde die Zusammensetzung des Darmmikrobioms bestimmt, im Plasma und in der Zerebrospinalflüssigkeit das Metabolitprofil untersucht und durch molekulare Analysen ergänzt. Sowohl die HFD-Fütterung als auch die LGG-Applikation führten zu geschlechtsspezifischen Unterschieden. Während LGG den diätinduzierten Anstieg von Plasmainsulin, ein erhöhtes Nebennierengewicht und Hyperaktivität in weiblichen Mäusen verhinderte, wurde das emotionale Verhalten nicht reguliert. Im Gegensatz dazu profitierte der Stoffwechsel männlicher Mäuse nicht von der LGG-Anwendung, jedoch war LGG in der Lage, spezifisch das depressiv-ähnliches Verhalten zu verbessern, was durch eine Analyse des zielgerichteten Verhaltens bestätigt wurde. Die Mikrobiomanalyse ergab, dass die Diät, jedoch nicht LGG, die Zusammensetzung des Darmmikrobioms in männlichen Mäusen verändert, was auf eine direkte Rolle von LGG in der Verhaltensregulation hindeutet. Im Vergleich dazu war das Darmmikrobiom in weiblichen Mäusen durch die Diät als auch durch LGG verändert, was zu den positiven Veränderungen der Stoffwechselparameter geführt haben könnte. Da weibliche Mäuse weder durch die HFD-Fütterung noch durch die LGG-Gabe einen Effekt auf emotionales Verhalten aufwiesen, wurden die Folgeanalysen bei männlichen Mäusen durchgeführt. Während die HFD-Fütterung das Vorkommen von Plasmalipiden veränderte, lagen aufgrund der LGG-Gabe verzweigtkettige Aminosäuren verringert vor, was mit einem verbessertem emotionalen Verhalten assoziierte. In den dopaminergen Gehirnregionen Nucleus Accumbens (NAcc) und VTA/SN revertierte LGG die HFD-induzierte Reduktion der Tyrosinhydroxylase Genexpression, des geschwindigkeitsbegrenzenden Enzyms in der Dopaminsynthese. Abschließend wurde eine Transkriptomanalyse mittels RNA Sequencing durchgeführt, welche die Genexpression von Cholezystokinin im NAcc als potenzieller Mediator in der Wirkung von LGG bei HFD-induzierten emotionalen Veränderungen identifizierte. Zusammenfassend konnten in dieser Arbeit die positiven Auswirkungen der LGG-Gabe auf emotionales Verhalten bei etablierter ernährungsbedingter Fettleibigkeit gezeigt werden.. Sowohl die HFD-Fütterung als auch die LGG-Gabe führten zu geschlechtsspezifischen Effekten, was zu Stoffwechselverbesserungen bei weiblichen Mäusen führte, während die LGG-Gabe das depressiv-ähnliche Verhalten bei männlichen Mäusen abschwächte. Zudem wurden auf Genexpressionsebene Tyrosinhydroxylase und Cholezystokinin identifiziert, die potentiell den Effekt von LGG auf das emotionale Verhalten in einem Modell etablierter ernährungsbedingter Fettleibigkeit vermitteln. KW - obesity KW - insulin resistance KW - probiotics KW - lactobacillus KW - depression KW - emotionality Y1 - 2022 ER - TY - JOUR A1 - Mumm, Rebekka A1 - Hermanussen, Michael T1 - A short note on the BMI and on secular changes in BMI JF - Human biology and public health N2 - Human size changes over time with worldwide secular trends in height, weight, and body mass index (BMI). There is general agreement to relate the state of nutrition to height and weight, and to ratios of weight-to-height. The BMI is a ratio. It is commonly used to classify underweight, overweight and obesity in adults. Yet, the BMI is inappropriate to provide any immediate information on body composition. It is accepted that the BMI is “a simple index to classify underweight, overweight and obesity in adults”. It is stated that “policies, programmes and investments need to be “nutrition-sensitive”, which means they must have positive impacts on nutrition”. It is also stated that “a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions“. But these statements are neither warranted by arithmetic considerations, nor by historic evidence. Measuring the BMI is an appropriate screening tool for detecting an unusual weight-to-height ratio, but the BMI is an inappropriate tool for estimating body composition, or suggesting medical and health policy decisions. KW - body mass index KW - secular trend KW - weight-to-height ratio KW - malnutrition KW - obesity Y1 - 2021 U6 - https://doi.org/10.52905/hbph.v2.17 SN - 2748-9957 IS - 2 PB - Universitätsverlag Potsdam CY - Potsdam ER - TY - JOUR A1 - Warschburger, Petra A1 - Gmeiner, Michaela A1 - Morawietz, Marisa A1 - Rinck, Mike T1 - Evaluation of an approach-avoidance training intervention for children and adolescents with obesity BT - a randomized placebo-controlled prospective trial JF - European eating disorders review : the professional journal of the Eating Disorders Associatio N2 - This study evaluated the efficacy of approach-avoidance training as an additional treatment for children and adolescents with obesity seeking inpatient treatment. Two hundred thirty-two participants (8-16years, 53.9% girls) were randomly assigned either to multisession approach-avoidance (IG) or to placebo training (CG). As outcomes, cognitive biases post intervention, body mass index, eating behaviour, food intake, self-regulation, and weight-related quality of life were assessed, also at 6- and 12-month follow-up. Modification of approach-avoidance bias was observed, but lacked in transfer over sessions and in generalization to attention and association bias. After 6months, the IG reported less problematic food consumption, higher self-regulation, and higher quality of life; effects did not persist until the 12-month follow-up; no significant interaction effects were observed regarding weight course. Despite there was no direct effect on weight course, approach-avoidance training seems to be associated with promising effects on important pillars for weight loss. Further research concerning clinical effectiveness is warranted. KW - approach-avoidance training KW - child KW - cognitive bias modification KW - intervention KW - obesity Y1 - 2018 U6 - https://doi.org/10.1002/erv.2607 SN - 1072-4133 SN - 1099-0968 VL - 26 IS - 5 SP - 472 EP - 482 PB - Wiley CY - Hoboken 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 - Warschburger, Petra T1 - Jugendliche und junge Erwachsene mit Adipositas T1 - Adolescents and Young Adults BT - Wie sollte in ihren Augen „die perfekte Therapie“ aussehen? BT - What Would a "Perfect Therapy" Look Like? JF - Die Rehabilitation : Zeitschrift für Praxis und Forschung in der Rehabilitation N2 - Hauptziel Adipositas ist eine der Hauptindikationen in der Kinder- und Jugend-Rehabilitation. Für ältere Jugendliche und junge Erwachsene fehlen altersspezifische Therapieangebote fast vollständig. Ziel war es die Wünsche bezüglich der Inhalte und Methoden einer „perfekten Therapie“ im Rahmen eines Rehabilitationsaufenthalts zu untersuchen. Methode Im Rahmen der YOUTH-Studie wurden 147 adipöse Jugendliche und junge Erwachsene beiderlei Geschlechts (zwischen 15 und 21 Jahren) mithilfe eines standardisierten Fragebogens befragt. Ergebnis Insgesamt zeigten sich relativ wenige alters- und geschlechtsspezifische Unterschiede. Interdisziplinär geleitete, koedukative Gruppen mit Elterneinbindung wurden gewünscht. Wichtige Themen waren gesunde Ernährung sowie psychosoziale Aspekte. Auch der Prävention von Rückfällen wurde eine hohe Relevanz zugeschrieben. Schlussfolgerung Psychosoziale Aspekte und die Vorbereitung auf mögliche Rückfallsituationen sollten integraler Bestandteil der Therapie sein. N2 - Principal objective Obesity is a major indication for pediatric and adolescent-rehabilitation. Age-specific therapies for „emerging adults“ are lacking. The aim was to examine the patients’ preferences with respect to the contents and methods of the „perfect therapy“ within an inpatient setting. Method In the context of the YOUTH study 147 obese male and female adolescents (aged 15–21 years) filled in standardized questionnaires. Results Overall little age- and gender-specific differences were observed. The participants expressed a preference for interdisciplinary coordinated and coeducational group approaches with involvement of the parents. Major topics were healthy nutrition and psychosocial aspects. Prevention of relapses is considered as important as well. Conclusion Psychosocial aspects and preparing coping with risk situations should be an integral part of treatment programs. KW - obesity KW - adolescents KW - young adults KW - therapy KW - requirements KW - Jugendliche KW - junge Erwachsene KW - Therapie KW - Anforderungen KW - Adipositas Y1 - 2017 U6 - https://doi.org/10.1055/s-0043-107930 SN - 0034-3536 SN - 1439-1309 VL - 57 IS - 5 SP - 295 EP - 302 PB - Thieme CY - Stuttgart ER - TY - JOUR A1 - Castaño Martínez, María Teresa A1 - Schumacher, Fabian A1 - Schumacher, Silke A1 - Kochlik, Bastian A1 - Weber, Daniela A1 - Grune, Tilman A1 - Biemann, Ronald A1 - McCann, Adrian A1 - Abraham, Klaus A1 - Weikert, Cornelia A1 - Kleuse, Burkhard A1 - Schürmann, Annette A1 - Laeger, Thomas T1 - Methionine restriction prevents onset of type 2 diabetes in NZO mice JF - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology N2 - Dietary methionine restriction (MR) is well known to reduce body weight by increasing energy expenditure (EE) and insulin sensitivity. An elevated concentration of circulating fibroblast growth factor 21 (FGF21) has been implicated as a potential underlying mechanism. The aims of our study were to test whether dietary MR in the context of a high-fat regimen protects against type 2 diabetes in mice and to investigate whether vegan and vegetarian diets, which have naturally low methionine levels, modulate circulating FGF21 in humans. New Zealand obese (NZO) mice, a model for polygenic obesity and type 2 diabetes, were placed on isocaloric high-fat diets (protein, 16 kcal%; carbohydrate, 52 kcal%; fat, 32 kcal%) that provided methionine at control (Con; 0.86% methionine) or low levels (0.17%) for 9 wk. Markers of glucose homeostasis and insulin sensitivity were analyzed. Among humans, low methionine intake and circulating FGF21 levels were investigated by comparing a vegan and a vegetarian diet to an omnivore diet and evaluating the effect of a short-term vegetarian diet on FGF21 induction. In comparison with the Con group, MR led to elevated plasma FGF21 levels and prevented the onset of hyperglycemia in NZO mice. MR-fed mice exhibited increased insulin sensitivity, higher plasma adiponectin levels, increased EE, and up-regulated expression of thermogenic genes in subcutaneous white adipose tissue. Food intake and fat mass did not change. Plasma FGF21 levels were markedly higher in vegan humans compared with omnivores, and circulating FGF21 levels increased significantly in omnivores after 4 d on a vegetarian diet. These data suggest that MR induces FGF21 and protects NZO mice from high-fat diet-induced glucose intolerance and type 2 diabetes. The normoglycemic phenotype in vegans and vegetarians may be caused by induced FGF21. MR akin to vegan and vegetarian diets in humans may offer metabolic benefits via increased circulating levels of FGF21 and merits further investigation.-Castano-Martinez, T., Schumacher, F., Schumacher, S., Kochlik, B., Weber, D., Grune, T., Biemann, R., McCann, A., Abraham, K., Weikert, C., Kleuser, B., Schurmann, A., Laeger, T. Methionine restriction prevents onset of type 2 diabetes in NZO mice. KW - energy expenditure KW - hyperglycemia KW - obesity KW - vegan KW - vegetarian Y1 - 2019 U6 - https://doi.org/10.1096/fj.201900150R SN - 0892-6638 SN - 1530-6860 VL - 33 IS - 6 SP - 7092 EP - 7102 PB - Federation of American Societies for Experimental Biology CY - Bethesda ER - TY - THES A1 - Henkel-Oberländer, Janin T1 - Einfluss von Prostaglandin E2 auf die Entstehung von Insulinresistenz und die Regulation der Entzündungsantwort bei der Diät-induzierten nicht-alkoholischen Fettlebererkrankung N2 - Weltweit sind fast 40 % der Bevölkerung übergewichtig und die Prävalenz von Adipositas, Insulinresistenz und den resultierenden Folgeerkrankungen wie dem Metabolischen Syndrom und Typ-2-Diabetes steigt rapide an. Als häufigste Ursachen werden diätetisches 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 häufigste Ursache für Leberfunktionsstörungen. Die Erkrankung umfasst sowohl die benigne hepatische Steatose (Fettleber) als auch die progressive Form der nicht-alkoholischen Steatohepatitis (NASH), bei der die Steatose von Entzündung und Fibrose begleitet ist. Die Ausbildung einer NASH erhöht das Risiko, ein hepatozelluläres Karzinom (HCC) zu entwickeln und kann zu irreversibler Leberzirrhose und terminalem Organversagen führen. Nahrungsbestandteile wie Cholesterol und Fett-reiche Diäten werden als mögliche Faktoren diskutiert, die den Übergang einer einfachen Fettleber zur schweren Verlaufsform der Steatohepatitis / NASH begünstigen. Eine Ausdehnung des Fettgewebes wird von Insulinresistenz und einer niedrig-gradigen chronischen Entzündung des Fettgewebes begleitet. Neben Endotoxinen aus dem Darm gelangen Entzündungsmediatoren aus dem Fettgewebe zur Leber. Als Folge werden residente Makrophagen der Leber, die Kupfferzellen, aktiviert, die eine Entzündungsantwort initiieren und weitere pro-inflammatorische Mediatoren freisetzen, zu denen Chemokine, Cytokine und Prostanoide wie Prostaglandin E2 (PGE2) gehören. In dieser Arbeit soll aufgeklärt werden, welchen Beitrag PGE2 an der Ausbildung von Insulinresistenz, hepatischer Steatose und Entzündung im Rahmen von Diät-induzierter NASH im komplexen Zusammenspiel mit der Regulation der Cytokin-Produktion und anderen Co-Faktoren wie Hyperinsulinämie und Hyperlipidämie hat. In murinen und humanen Makrophagen-Populationen wurde untersucht, welche Faktoren die Bildung von PGE2 fördern und wie PGE2 die Entzündungsantwort aktivierter Makrophagen reguliert. In primären 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-abhängige 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 Mäuse, in denen die PGE2-Synthese durch die Deletion der mikrosomalen PGE-Synthase 1 (mPGES1) vermindert war, mit einer NASH-induzierenden Diät gefüttert. In Lebern von Patienten mit NASH oder in Mäusen mit Diät-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 primären 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 verstärkt, wenn die Zellen mit Endotoxinen wie Lipopolysaccharid (LPS), Fettsäuren wie Palmitinsäure, Cholesterol und Cholesterol-Kristallen oder Insulin, das als Folge der kompensatorischen Hyperinsulinämie bei Insulinresistenz verstärkt freigesetzt wird, inkubiert wurden. Insulin steigerte dabei synergistisch mit LPS oder Palmitinsäure die Synthese von PGE2 sowie der anderen Entzündungsmediatoren wie Interleukin (IL) 8 und IL-1β. PGE2 reguliert die Entzündungsantwort: Neben der Induktion der eigenen Synthese-Enzyme verstärkte 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 Verstärkung der Entzündungsreaktion beitragen. Außerdem förderte PGE2 die Bildung von Oncostatin M (OSM) und OSM induzierte in einer positiven Rückkopplungsschleife 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 Entzündungsreaktion abschwächen. In primären Hepatozyten der Ratte und humanen Hepatozyten beeinträchtigte PGE2 direkt die Insulin-abhängige 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 verstärkte außerdem die IL-6- oder OSM-vermittelte Insulinresistenz und Steatose in primären Hepatozyten der Ratte. Die Wirkung von PGE2 im Gesamtorganismus sollte in Mäusen mit Diät-induzierter NASH untersucht werden. Die Fütterung einer Hochfett-Diät mit Schmalz als Fettquelle, das vor allem gesättigte Fettsäuren enthält, verursachte Fettleibigkeit, Insulinresistenz und eine hepatische Steatose in Wildtyp-Mäusen. In Tieren, die eine Hochfett-Diät mit Sojaöl als Fettquelle, das vor allem (ω-6)-mehrfach-ungesättigte Fettsäuren (PUFAs) enthält, oder eine Niedrigfett-Diät mit Cholesterol erhielten, war lediglich eine hepatische Steatose nachweisbar, jedoch keine verstärkte Gewichtszunahme im Vergleich zu Geschwistertieren, die eine Standard-Diät bekamen. Im Gegensatz dazu verursachte die Fütterung einer Hochfett-Diät mit PUFA-reichem Sojaöl als Fettquelle in Kombination mit Cholesterol sowohl Fettleibigkeit und Insulinresistenz als auch hepatische Steatose mit Hepatozyten-Hypertrophie, lobulärer Entzündung und beginnender Fibrose in Wildtyp-Mäusen. Diese Tiere spiegelten alle klinischen und histologischen Parameter der humanen NASH im Metabolischen Syndrom wider. Nur die Kombination von hohen Mengen ungesättigter Fettsäuren aus Sojaöl und Cholesterol in der Nahrung führte zu einer exzessiven Akkumulation des Cholesterols und der Bildung von Cholesterol-Kristallen in den Hepatozyten, die zur Schädigung der Mitochondrien, schwerem oxidativem Stress und schließlich zum Absterben der Zellen führten. Als Konsequenz phagozytieren Kupfferzellen die Zelltrümmer der Cholesterol-überladenen Hepatozyten, werden dadurch aktiviert, setzen Chemokine, Cytokine und PGE2 frei, die die Entzündungsreaktion verstärken und die Infiltration von weiteren Immunzellen initiieren können und verursachen so eine Progression zur Steatohepatitis (NASH). Die Deletion der mikrosomalen PGE-Synthase 1 (mPGES1), dem induzierbaren Enzym der PGE2-Synthese aus Cyclooxygenase-abhängigen Vorstufen, reduzierte die Diät-abhängige Bildung von PGE2 in der Leber. Die Fütterung der NASH-induzierenden Diät verursachte in Wildtyp- und mPGES1-defizienten Mäusen eine ähnliche Fettleibigkeit und Zunahme der Fettmasse sowie die Ausbildung von hepatischer Steatose mit Entzündung und Fibrose (NASH) im histologischen Bild. In mPGES1-defizienten Mäusen waren jedoch Parameter für die Infiltration von Entzündungszellen und die Diät-abhängige Schädigung der Leber im Vergleich zu Wildtyp-Tieren erhöht, was sich auch in einer stärkeren Diät-induzierten systemischen Insulinresistenz widerspiegelte. Die Bildung des pro-inflammatorischen und pro-apoptotischen Cytokins TNFα war in mPGES1-defizienten Mäusen durch die Aufhebung der negativen Rückkopplungshemmung verstärkt, was einen gesteigerten Diät-induzierten Zelluntergang gestresster Lipid-überladener Hepatozyten und eine nach-geschaltete Entzündungsantwort zur Folge hatte. Zusammenfassend wurde unter den gewählten Versuchsbedingungen in vivo eine anti-inflammatorische Rolle von PGE2 verifiziert, da das Prostanoid vor allem indirekt durch die Hemmung der TNFα-vermittelten Entzündungsreaktion die Schädigung der Leber, die Verstärkung der Entzündung und die Ausbildung von Insulinresistenz im Rahmen der Diät-abhängigen Fettlebererkrankung abschwächte. N2 - Obesity is a worldwide problem affecting almost 40 % of the population. The prevalence of obesity, insulin resistance and the consequent diseases such as type-2-diabetes and metabolic syndrome is increasing rapidly. The main underlying reasons are high caloric diets and reduced physical exercise. The incidence of non-alcoholic fatty liver disease (NAFLD), characterized by hepatic lipid accumulation, is correlated with the body mass index. NAFLD is generally considered to be the hepatic manifestation of metabolic syndrome and is the most frequent cause of functional disorders of the liver. NAFLD comprises both the mild form of benign hepatic steatosis (fatty liver) as well as the progressive form of non-alcoholic steatohepatitis (NASH), in which hepatic steatosis is accompanied by inflammation and fibrosis. The development of NASH may result in hepatocellular carcinoma, liver cirrhosis and terminal organ failure. High fat diets and dietary cholesterol might impact the transistion from fatty liver to NASH. The diet induced expansion of the white adipose tissue is associated with the development of insulin resistance as well as low-grade chronic inflammation. Inflammatory mediators from the adipose tissue in combination with dietary components from the gut reach the liver and activate Kupffer cells, the resident liver macrophages. As a consequence, macrophages initiate an inflammatory response that involves secretion of immune cell recruiting chemokines, pro-inflammatory cytokines and prostanoids like prostaglandin E2 (PGE2). The aim of the study was to elucidate the impact of PGE2 in the development of insulin resistance, hepatic steatosis and inflammation in diet-induced NASH. These processes implicate a complex interplay of various cell types in the liver, the PGE2-mediated regulation of cytokine synthesis, as well as factors like hyperinsulinemia and hyperlipidemia. In vitro studies with murine and human macrophage populations characterise the generation of PGE2 and the PGE2-mediated regulation of the inflammatory response. Primary rat and human hepatocytes, in addition to immortal cell lines, were incubated with PGE2 alone and in combination with PGE2-dependent generated cytokines. The intent of this experimental series was to clarify the impact of these mediators on the activation of the insulin signaling chain and resulting metabolic processes in glucose and lipid metabolism. The role of PGE2 in vivo was examined in mice with reduced PGE2 synthesis due to the genetic deletion of microsomal PGE synthase 1 (mPGES1), which were additionally fed a NASH-inducing diet. The hepatic expression of the PGE2-generating enzymes cyclooxygenase 2 (COX2) and mPGES1 was increased in mice with diet-induced NASH as well as in liver biopsies of patients with NASH compared to patients with simple hepatic steatosis or non-steatotic controls, indicating an enlarged capacity for PGE2 synthesis in NASH. Furthermore, the expression of COX2 and mPGES1 in the human study cohort correlated with the severity of the hepatic disease.. Treatment of macrophages with endotoxins like lipopolysaccharide (LPS), fatty acids like palmitic acid, cholesterol and cholesterol crystals, or insulin, which is released as a consequence of insulin resistance in the context of a compensatory hyperinsulinemia, resulted in an enhanced production of pro-inflammatory mediators such as chemokines, cytokines and PGE2. A combinatory treatment of human macrophages with insulin and LPS or palmitic acid induced a synergistic increase in PGE2 synthesis and production of interleukins (IL) like IL-8 and IL-1β. PGE2 itself modulates the inflammatory response: The prostanoid induced the enzymes involved in its own synthesis, in addition to immune cell recruiting chemokines such as IL-8 and (C-C-motiv) ligand 2 (CCL2), and pro-inflammatory cytokines such as IL-1β and IL-6 in macrophages. This may result in an amplification of the inflammatory response. Furthermore, PGE2 induced the production of oncostatin M (OSM), which in turn enhanced the expression of the enzymes generating PGE2 in a positive feedback loop. On the other hand, PGE2 inhibited the basal and LPS-mediated synthesis of the potent pro-inflammatory cytokine tumor necrosis factor α (TNFα). This may result in a reduced inflammatory response. In primary rat and human hepatocytes PGE2 directly interfered with the insulin mediated activation of the insulin receptor signaling chain and impaired glucose utilisation. Mechanistically, through interaction with different PGE2 receptors, PGE2 activated serine kinases including ERK1/2 and IKKβ, which cause inhibitory phosphorylations at serine residues of the insulin receptor substrates and force their degradation. PGE2 enhanced the insulin resistance and increased hepatic steatosis induced by IL-6 or OSM in primary rat hepatocytes. A murine model of diet-induced NASH was established to elucidate the impact of PGE2 in the complex in vivo regulation. Lard-based high fat diets containing mainly saturated fatty acids initiated a strong body weight gain, obesity, insulin resistance and hepatic steatosis without further damage of the liver in mice. Furthermore, mice fed a high fat diet based on soybean oil with high amounts of (ω-6)-poly-unsaturated fatty acids (PUFAs) or a low fat diet with high cholesterol did not result in increased body weight gain compaired to mice fed a chow (low fat) diet, but did cause mild hepatic steatosis. In contrast, mice fed a high fat diet based on PUFA-rich soybean oil in combination with high dietary cholesterol caused body weight gain, obesity, insulin resistance and hepatic steatosis accompanied by hepatocyte hypertrophy, lobular inflammation and fibrosis in wildtype mice. This dietary model displayed all clinical and histological parameters of human NASH in the metabolic syndrome. Only the combination of soybean oil derived fatty acids and dietary cholesterol provoked an excessive accumulation of cholesterol in hepatocytes and the generation of cholesterol crystals that caused mitochondrial damage, severe oxidative stress, and subsequently hepatocyte death. Hepatic macrophages phagocytose hepatocyte debris, lipids and cholesterol crystals and thereby were activated to produce pro-inflammatory mediators like chemokines, cytokines and prostanoids like PGE2 that initiate an inflammatory response. This included immune cell infiltration, inflammation and fibrogenic processes that determine the progression to steatohepatitis (NASH). The deletion of microsomal PGE synthase 1 (mPGES1), the inducible enzyme generating PGE2 from COX2 derived PGH2, reduced the diet-dependent increase in hepatic PGE2 production in mice fed a NASH-inducing diet. While body weight gain, obesity and histological parameters of NASH including steatosis, inflammation and fibrosis were comparable in wild type and mPGES1-deficient mice fed a NASH inducing diet, parameters of immune cell infiltration and hepatic damage were augmented only in mPGES1-deficient mice. This results in a more pronounced diet-induced glucose intolerance and insulin resistance index in mPGES1-deficient mice compared to wild type littermates. In parallel, hepatic production of the potent pro-inflammatory and pro-apoptotic cytokine TNFα was enhanced in mice with the deletion of mPGES1 due to the abolished PGE2-mediated negative feedback loop. This was accompanied by increased diet induced cell death of lipid loaded stressed hepatocytes and could result in an intensified inflammatory response. In summary, in vivo studies verify an anti-inflammatory role of PGE2. The prostanoid PGE2 acts mainly indirectly and could attenuate the TNFα-mediated liver damage, immune response and the resulting insulin resistance in the context of diet induced fatty liver diseases. KW - Prostaglandine KW - Entzündung KW - Insulin KW - Leber KW - Fettleibigkeit KW - prostaglandins KW - inflammation KW - insulin KW - liver KW - obesity Y1 - 2021 ER -