TY  - JOUR
A1  - Hocher, Berthold
A1  - Heimerl, Dirk
A1  - Slowinski, Torsten
A1  - Godes, Michael
A1  - Halle, Horst
A1  - Priem, Friedrich
A1  - Pfab, Thiemo
T1  - Birthweight and Fetal Glycosylated Hemoglobin at Birth in Newborns Carrying the GLUT1 XbaI Gene Polymorphism
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: Low birthweight is an independent risk factor of glucose intolerance and type 2 diabetes in later life. Genetically determined insulin resistance and subsequently impaired glucose uptake might explain both reduced fetal growth and elevated blood glucose. The glucose transporter 1 (GLUT!) plays an important role for fetal glucose uptake as well as for maternal-fetal glucose transfer, and it has been associated with insulin resistance in adults. The present study hypothesized that the common fetal GLUT1 XbaI polymorphism might reduce fetal insulin sensitivity and/or glucose supply in utero, thus affecting fetal blood glucose and fetal growth.
 Methods: A genetic association study was conducted at the obstetrics department of the Charite University Hospital, Berlin, Germany. 119.1 white women were included after delivery, and all newborns were genotyped for the GLUT1 XbaI polymorphism. Total glycosylated hemoglobin was quantified, serving as a surrogate of glycemia during the last weeks of pregnancy.
 Results: The analysis of this large population showed no significant differences in fetal glycosylated hemoglobin or birthweight for the different fetal GLUT1 XbaI genotypes. Only newborns carrying the mutated allele show the previously published inverse association between birthweight and glycosylated hemoglobin.
 Conclusions: The results suggest that there is no prenatal effect of the fetal GLUT1 XbaI polymorphism on fetal insulin sensitivity, intrauterine fetal glucose supply or fetal growth. However, the polymorphism seems to modulate the inverse interaction between birthweight and fetal glycemia.
KW  - GLUT1 XbaI gene polymorphism
KW  - birthweight
KW  - total glycosylated hemoglobin
KW  - insulin resistance
KW  - fetal programming
Y1  - 2011
SN  - 1433-6510
VL  - 57
IS  - 9-10
SP  - 651
EP  - 657
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Kleuser, Burkhard
T1  - Divergent role of sphingosine 1-phosphate in liver health and disease
JF  - International journal of molecular sciences
N2  - Two decades ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule that regulates a variety of cellular functions. The plethora of S1P-mediated effects is due to the fact that the sphingolipid not only modulates intracellular functions but also acts as a ligand of G protein-coupled receptors after secretion into the extracellular environment. In the plasma, S1P is found in high concentrations, modulating immune cell trafficking and vascular endothelial integrity. The liver is engaged in modulating the plasma S1P content, as it produces apolipoprotein M, which is a chaperone for the S1P transport. Moreover, the liver plays a substantial role in glucose and lipid homeostasis. A dysfunction of glucose and lipid metabolism is connected with the development of liver diseases such as hepatic insulin resistance, non-alcoholic fatty liver disease, or liver fibrosis. Recent studies indicate that S1P is involved in liver pathophysiology and contributes to the development of liver diseases. In this review, the current state of knowledge about S1P and its signaling in the liver is summarized with a specific focus on the dysregulation of S1P signaling in obesity-mediated liver diseases. Thus, the modulation of S1P signaling can be considered as a potential therapeutic target for the treatment of hepatic diseases.
KW  - sphingolipids
KW  - sphingosine kinase
KW  - fibrosis
KW  - non-alcoholic fatty liver disease
KW  - insulin resistance
KW  - liver fibrosis
Y1  - 2018
U6  - https://doi.org/10.3390/ijms19030722
SN  - 1422-0067
VL  - 19
IS  - 3
PB  - MDPI
CY  - Basel
ER  - 
TY  - THES
A1  - Gonzalez Camargo, Rodolfo
T1  - Insulin resistance in cancer cachexia and metabolic syndrome
BT  - role of insulin activated macrophages and miRNA-21-5p
N2  - The ever-increasing fat content in Western diet, combined with decreased levels of physical activity, greatly enhance the incidence of metabolic-related diseases. Cancer cachexia (CC) and Metabolic syndrome (MetS) are both multifactorial highly complex metabolism related syndromes, whose etiology is not fully understood, as the mechanisms underlying their development are not completely unveiled. Nevertheless, despite being considered “opposite sides”, MetS and CC share several common issues such as insulin resistance and low-grade inflammation. In these scenarios, tissue macrophages act as key players, due to their capacity to produce and release inflammatory mediators. One of the main features of MetS is hyperinsulinemia, which is generally associated with an attempt of the β-cell to compensate for diminished insulin sensitivity (insulin resistance). There is growing evidence that hyperinsulinemia per se may contribute to the development of insulin resistance, through the establishment of low grade inflammation in insulin responsive tissues, especially in the liver (as insulin is secreted by the pancreas into the portal circulation). The hypothesis of the present study was that insulin may itself provoke an inflammatory response culminating in diminished hepatic insulin sensitivity. To address this premise, firstly, human cell line U937 differentiated macrophages were exposed to insulin, LPS and PGE2. In these cells, insulin significantly augmented the gene expression of the pro-inflammatory mediators IL-1β, IL-8, CCL2, Oncostatin M (OSM) and microsomal prostaglandin E2 synthase (mPGES1), and of the anti-inflammatory mediator IL-10. Moreover, the synergism between insulin and LPS enhanced the induction provoked by LPS in IL-1β, IL-8, IL-6, CCL2 and TNF-α gene. When combined with PGE2, insulin enhanced the induction provoked by PGE2 in IL-1β, mPGES1 and COX2, and attenuated the inhibition induced by PGE2 in CCL2 and TNF-α gene expression contributing to an enhanced inflammatory response by both mechanisms. Supernatants of insulin-treated U937 macrophages reduced the insulin-dependent induction of glucokinase in hepatocytes by 50%. Cytokines contained in the supernatant of insulin-treated U937 macrophages also activated hepatocytes ERK1/2, resulting in inhibitory serine phosphorylation of the insulin receptor substrate. Additionally, the transcription factor STAT3 was activated by phosphorylation resulting in the induction of SOCS3, which is capable of interrupting the insulin receptor signal chain. MicroRNAs, non-coding RNAs linked to protein expression regulation, nowadays recognized as active players in the generation of several inflammatory disorders such as cancer and type II diabetes are also of interest. Considering that in cancer cachexia, patients are highly affected by insulin resistance and inflammation, control, non-cachectic and cachectic cancer patients were selected and the respective circulating levels of pro-inflammatory mediators and microRNA-21-5p, a posttranscriptional regulator of STAT3 expression, assessed and correlated. Cachectic patients circulating cytokines IL-6 and IL-8 levels were significantly higher than those of non-cachectic and controls, and the expression of microRNA-21-5p was significantly lower. Additionally, microRNA-21-5p reduced expression correlated negatively with IL-6 plasma levels. These results indicate that hyperinsulinemia per se might contribute to the low grade inflammation prevailing in MetS patients and thereby promote the development
of insulin resistance particularly in the liver. Diminished MicroRNA-21-5p expression may enhance inflammation and STAT3 expression in cachectic patients, contributing to the development of insulin resistance.
N2  - O teor de gordura cada vez maior na dieta ocidental, combinada com a diminuição dos níveis de atividade física têm marcadamente aumentado à incidência de doenças relacionas ao metabolismo. A caquexia associada ao câncer (CC) e a síndrome metabólica (SM) são síndromes de etiologia complexa e multifatorial, não totalmente compreendida, e com mecanismos subjacentes ao seu desenvolvimento não completamente revelados. No entanto, apesar de serem consideradas "lados opostos", a CC e a MetS apresentam várias características em comum, tais como resistência à insulina e inflamação de baixo grau, com macrófagos teciduais como importantes coadjuvantes, devido à sua capacidade de produzir e liberar mediadores inflamatórios, e microRNAs, descritos como RNAs não-codificantes ligados à regulação da expressão de proteínas e reconhecidos como participantes ativos na geração de várias doenças inflamatórias, tais como o câncer e diabetes tipo II. Uma das principais características da MetS é a hiperinsulinemia, que está geralmente associada com uma tentativa da célula β do pâncreas de compensar a diminuição da sensibilidade à insulina (resistência à insulina). Um número crescente de evidências sugere que a hiperinsulinemia “por si só”, pode contribuir com o desenvolvimento de resistência à insulina através do estabelecimento de um quadro inflamatório de baixo grau, em tecidos sensíveis a insulina, e em particular no fígado, devido ao fato da insulina ser secretada pelo pâncreas na circulação portal. A hipótese do presente estudo foi que a insulina pode induzir uma resposta inflamatória em macrófagos e culminar em diminuição da sensibilidade hepática à insulina. Para confirmar esta hipótese, primeiramente, macrófagos diferenciados da linhagem de células humanas U937 foram expostos à insulina, LPS e PGE2. Nestas células, a insulina aumentou significativamente a expressão gênica dos mediadores pró-inflamatórios IL-1β, IL- 8, CCL2, oncostatina M (OSM) e prostaglandina E2 sintase microssomal (mPGES1), e do mediador anti-inflamatório IL-10. Além disso, o sinergismo entre insulina e LPS aumentou a indução provocada por LPS nos genes da IL-1β, IL-8, IL-6, CCL2 e TNF-α. Quando combinado com PGE2, a insulina aumentou a indução provocada pela PGE2 nos genes da IL-1β, mPGES1 e COX2, e restaurou a inibição induzida pela PGE2 no gene CCL2 e TNF-α.Subsequentemente, sobrenadantes dos macrófagos U937 tratados com insulina modulou negativamente a sinalização da insulina em culturas primárias de hepatócitos de rato, como observado pela atenuação de 50% da indução dependente de insulina da enzima glicoquinase. Citocinas contidas no sobrenadante de macrófagos U937 tratados com insulina também ativaram em hepatócitos ERK1/2, resultando na fosforilação do resíduo de serina inibitório do substrato do receptor de insulina. Adicionalmente, o fator de transcrição STAT3 foi ativado por um elevado grau de fosforilação e a proteína SOCS3, capaz de interromper a via de sinalização do receptor de insulina, foi induzida. Considerando que na caquexia associada ao câncer, pacientes são altamente afetados pela resistência à insulina e inflamação, pacientes controle, não caquéticos e caquéticos foram seleccionados e os respectivos níveis circulantes de mediadores pró-inflamatórios e microRNA-21-5p, um regulador pós-transcricional da expressão de STAT3, avaliados e correlacionados. Pacientes caquéticos exibiram citocinas circulantes IL-6 e IL-8 significativamente maiores do que pacientes não caquéticos e controles, assim como a expressão de microRNA-21-5p significativamente diminuida. Além disso, a reduzida expressão de microRNA-21-5p correlaciona-se negativamente com níveis de IL-6 no plasma. Estes resultados indicam que a hiperinsulinemia pode, por si só contribuir para o desenvolvimento da inflamação de baixo grau prevalente em pacientes com excesso de peso e obesos e, assim, promover o desenvolvimento de resistência à insulina especialmente no fígado e o nível reduzido de miRNA-21-5p pode modular a inflamação e expressão de STAT3 em pacientes caquéticos, contribuindo para o desenvolvimento da resistência à insulina.
N2  - Der stetig steigende Fettgehalt in westlicher Ernährung in Kombination mit reduzierter körperlicher Aktivität hat zu einem dramatischen Anstieg der Inzidenz metabolischer Erkrankungen geführt. Tumorkachexie (Cancer cachexia, CC) und Metabolisches Syndrom (MetS) sind sehr komplexe, multifaktorielle metabolische Erkrankungen, deren Ätiologie nicht vollständig verstanden ist. Die molekularen Ursachen, die zu diesen Symptomkomplexen führen, sind noch unzureichend aufgeklärt. Obwohl ihr äußeres Erscheinungsbild stark gegensätzlich ist, haben MetS und CC etliche Gemeinsamkeiten wie zum Beispiel Insulinresistenz und eine chronische unterschwellige Entzündung. Sowohl bei der Entstehung der Insulinresistenz als auch bei der chronischen Entzündung spielen Makrophagen eine Schlüsselrolle, weil sie in der Lage sind pro-inflammatorische Mediatoren zu produzieren und freizusetzen.
Eine der hervorstechendsten Auffälligkeiten des MetS ist die Hyperinsulinämie, die durch den Versuch der β-Zelle, die verminderte Insulinsensitivität (Insulinresistenz) zu kompensieren, zustande kommt. Es gibt zunehmend Hinweise darauf, dass die Hyperinsulinämie selber an der Entzündungsentstehung in Insulin-abhängigen Geweben beteiligt ist und dadurch zur Entwicklung und Verstärkung der Insulinresistenz beitragen kann. Dies trifft besonders auf die Leber zu, weil hier die Insulinspiegel besonders hoch sind, da Insulin vom Pankreas direkt in den Pfortaderkeislauf gelangt. Daher wurde in dieser Arbeit die Hypothese geprüft, ob Insulin selber eine Entzündungsantwort auslösen und dadurch die hepatische Insulinsensitivität senken kann. Zu diesem Zweck wurde die humane Zelllinie U937 durch PMA-Behandlung zu Makrophagen differenziert und diese Makrophagen mit Insulin, LPS und PGE2 inkubiert. In diesen Zellen steigerte Insulin die Expression der pro-inflammatorischen Mediatoren IL-1β, IL-8, CCL2, Oncostatin M (OSM) signifikant und induzierte die mikrosomale PGE-Synthase 1 (mPGES1) ebenso wie das antiinflammatorische Cytokin IL-10. Ferner verstärkte Insulin die LPS-abhängige Induktion des IL-1β-, IL-8-, IL-6-, CCL2- und TNFα-Gens. Ebenso verstärkte Insulin die PGE2-abhängige Induktion von IL-1β, mPGES1 und COX2. Im Gegensatz dazu schwächte es die Hemmende Wirkung von PGE2 auf Expression von TNFα und CCL2 ab und trug so auf beide Weisen zu einer Verstärkung der Entzündungsantwort bei. Überstände von Insulin-behandelten U937 Makrophagen reduzierten die Insulin-abhängige Induktion der Glukokinase in Hepatocyten um 50%. Die Cytokine, die im Überstand Insulin-behandelter Makrophagen enthalten waren, aktivierten in Hepatocyten ERK1/2, was zu einer inhibitorischen Serin-Phosphorylierung der Insulin Rezeptor Substrats (IRS) führte. Zusätzlich führten die Cytokine zu einer Phosphorylierung und Aktivierung von STAT3 und einer dadurch bedingten Induktion von SOCS3, das seinerseits die Insulinrezeptor-Signalkette unterbrechen kann.
MicroRNAs, nicht-codierende RNAs, die an der Regulation der Proteinexpression beteiligt sind und deren Beteiligung an der Regulation der Entzündungsantwort bei zahlreichen Erkrankungen, unter anderem Tumorerkrankungen und Typ II Diabetes gezeigt wurde, sind auch von Interesse. Unter dem Blickwinkel, dass Tumor-Kachexie Patienten sich durch eine Insulinresistenz und eine systemische Entzündung auszeichnen, wurden in nichtkachektische und tumorkachektische Patienten Plasmaspiegel von pro-inflammatorischen Mediatoren und der microRNA-21-5p bestimmt, von der bekannt ist, dass sie ein posttranskriptioneller Regulator der STAT3 Expression ist. Die Spiegel der proinflammatorischen Mediatoren und der miRNA-21-5p wurden korreliert. In kachektischen Patienten waren die Spiegel der Cytokine IL-6 und IL-8 signifikant höher, die der miRNA-21- 5p signifikant niedriger als in nicht-kachektischen Patienten. Die Plasma IL-6-Spiegel korrelierten negativ mit den miRNA21-5p Spiegeln.
Insgesamt zeigen die Ergebnisse, dass eine Hyperinsulinämie selber zu der Entwicklung einer unterschwellingen Entzündung, wie sie in Patienten mit einem MetS vorherrscht, beitragen, und dadurch besonders in der Leber eine Insulinresistenz auslösen oder verstärken kann. Eine verringerte Expression der MicroRNA-21-5p kann in kachektischen Patienten die Entzündungsantwort, im Speziellen die STAT3 Expression, verstärken und dadurch zur Entwicklung einer Insulinresistenz beitragen
KW  - cachexia
KW  - metabolic syndrome
KW  - inflammation
KW  - insulin resistance
KW  - microRNAs
KW  - insulin
KW  - liver
KW  - macrophages
KW  - caquexia
KW  - síndrome metabólica
KW  - inflamação
KW  - resistência à insulina
KW  - microRNAs
KW  - insulina
KW  - fígado
KW  - macrófagos
KW  - Kachexie
KW  - metabolisches Syndrom
KW  - Entzündung
KW  - Insulinresistenz
KW  - MicroRNAs
KW  - Insulin
KW  - Leber
KW  - Makrophagen
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-100973
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  - Fedders, Ronja
A1  - Muenzner, Matthias
A1  - Weber, Pamela
A1  - Sommerfeld, Manuela
A1  - Knauer, Miriam
A1  - Kedziora, Sarah
A1  - Kast, Naomi
A1  - Heidenreich, Steffi
A1  - Raila, Jens
A1  - Weger, Stefan
A1  - Henze, Andrea
A1  - Schupp, Michael
T1  - Liver-secreted RBP4 does not impair glucose homeostasis in mice
JF  - The journal of biological chemistry
N2  - Retinol-binding protein 4 (RBP4) is the major transport protein for retinol in blood. Recent evidence from genetic mouse models shows that circulating RBP4 derives exclusively from hepatocytes. Because RBP4 is elevated in obesity and associates with the development of glucose intolerance and insulin resistance, we tested whether a liver-specific overexpression of RBP4 in mice impairs glucose homeostasis. We used adeno-associated viruses (AAV) that contain a highly liver-specific promoter to drive expression of murine RBP4 in livers of adult mice. The resulting increase in serum RBP4 levels in these mice was comparable with elevated levels that were reported in obesity. Surprisingly, we found that increasing circulating RBP4 had no effect on glucose homeostasis. Also during a high-fat diet challenge, elevated levels of RBP4 in the circulation failed to aggravate the worsening of systemic parameters of glucose and energy homeostasis. These findings show that liver-secreted RBP4 does not impair glucose homeostasis. We conclude that a modest increase of its circulating levels in mice, as observed in the obese, insulin-resistant state, is unlikely to be a causative factor for impaired glucose homeostasis.
KW  - liver
KW  - retinoid-binding protein
KW  - glucose metabolism
KW  - insulin resistance
KW  - mouse
KW  - TTR
Y1  - 2018
U6  - https://doi.org/10.1074/jbc.RA118.004294
SN  - 1083-351X
VL  - 293
IS  - 39
SP  - 15269
EP  - 15276
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Li, Jian
A1  - Wang, Zi-Neng
A1  - Schlemm, Ludwig
A1  - Pfab, Thiemo
A1  - Xiao, Xiao-Min
A1  - Chen, You-Peng
A1  - Hocher, Berthold
T1  - Low birth weight and elevated head-to-abdominal circumference ratio are associated with elevated fetal glycated serum protein concentrations
JF  - Journal of hypertension
N2  - Objective To analyze the association between low birth weight, head-to-abdominal circumference ratio, and insulin resistance in early life.
 Method and results Glycated serum proteins (GSPs) were quantified at delivery in 612 Chinese mother/child pairs serving as a surrogate of maternal and fetal glycemia. Differential ultrasound examination of the fetal's body (head circumference, biparietal diameter, pectoral diameter, abdominal circumference, and femur length) was done in average 1 week prior to delivery. Multivariable regression analysis considering gestational age at delivery, the child's sex, maternal BMI, maternal age at delivery, maternal body weight, and pregnancyinduced hypertension revealed that fetal GSP was inversely associated with birth weight (R(2) = 0.416; P < 0.001). Fetal GSP was furthermore positively associated with the head-to-abdominal circumference ratio, whereas the maternal GSP was negatively correlated with the offspring's head-to-abdominal circumference ratio (R(2) = 0.285; P = 0.010 and R(2) = 0.261; P = 0.020, respectively). The increased head-to-abdominal circumference ratio in newborns with higher fetal GSP is mainly due to a reduced abdominal circumference rather than reduced growth of the brain.
 Conclusion The disproportional intrauterine growth is in line with the concept of so-called brain sparing, a mechanism maintaining the intrauterine growth of the brain at the expense of trunk growth. Our data suggest that the low birth weight phenotype, linked to cardiovascular diseases like hypertension in later life, might be a phenotype of disproportional intrauterine growth retardation and early life insulin resistance.
KW  - disproportional intrauterine growth retardation
KW  - insulin resistance
KW  - low birth weight
KW  - ultrasound
Y1  - 2011
U6  - https://doi.org/10.1097/HJH.0b013e328349a2e6
SN  - 0263-6352
VL  - 29
IS  - 9
SP  - 1712
EP  - 1718
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Tian, Mei
A1  - Reichetzeder, Christoph
A1  - Li, Jian
A1  - Hocher, Berthold
T1  - Low birth weight, a risk factor for diseases in later life, is a surrogate of insulin resistance at birth
JF  - Journal of hypertension
N2  - Low birth weight (LBW) is associated with diseases in adulthood. The birthweight attributed risk is independent of confounding such as gestational age, sex of the newborn but also social factors. The birthweight attributed risk for diseases in later life holds for the whole spectrum of birthweight. This raises the question what pathophysiological principle is actually behind the association. In this review, we provide evidence that LBW is a surrogate of insulin resistance. Insulin resistance has been identified as a key factor leading to type 2 diabetes, cardiovascular disease as well as kidney diseases. We first provide evidence linking LBW to insulin resistance during intrauterine life. This might be caused by both genetic (genetic variations of genes controlling glucose homeostasis) and/or environmental factors (due to alterations of macronutrition and micronutrition of the mother during pregnancy, but also effects of paternal nutrition prior to conception) leading via epigenetic modifications to early life insulin resistance and alterations of intrauterine growth, as insulin is a growth factor in early life. LBW is rather a surrogate of insulin resistance in early life - either due to inborn genetic or environmental reasons - rather than a player on its own.
KW  - epigenetics
KW  - fetal programing
KW  - genetics
KW  - insulin resistance
KW  - low birth weight
Y1  - 2019
U6  - https://doi.org/10.1097/HJH.0000000000002156
SN  - 0263-6352
SN  - 1473-5598
VL  - 37
IS  - 11
SP  - 2123
EP  - 2134
PB  - Kluwer
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Hauffe, Robert
A1  - Rath, Michaela
A1  - Agyapong, Wilson
A1  - Jonas, Wenke
A1  - Vogel, Heike
A1  - Schulz, Tim Julius
A1  - Schwarz, Maria
A1  - Kipp, Anna Patricia
A1  - Blüher, Matthias
A1  - Kleinridders, André
T1  - Obesity Hinders the Protective Effect of Selenite Supplementation on Insulin Signaling
JF  - Antioxidants
N2  - The intake of high-fat diets (HFDs) containing large amounts of saturated long-chain fatty acids leads to obesity, oxidative stress, inflammation, and insulin resistance. The trace element selenium, as a crucial part of antioxidative selenoproteins, can protect against the development of diet-induced insulin resistance in white adipose tissue (WAT) by increasing glutathione peroxidase 3 (GPx3) and insulin receptor (IR) expression. Whether selenite (Se) can attenuate insulin resistance in established lipotoxic and obese conditions is unclear. We confirm that GPX3 mRNA expression in adipose tissue correlates with BMI in humans. Cultivating 3T3-L1 pre-adipocytes in palmitate-containing medium followed by Se treatment attenuates insulin resistance with enhanced GPx3 and IR expression and adipocyte differentiation. However, feeding obese mice a selenium-enriched high-fat diet (SRHFD) only resulted in a modest increase in overall selenoprotein gene expression in WAT in mice with unaltered body weight development, glucose tolerance, and insulin resistance. While Se supplementation improved adipocyte morphology, it did not alter WAT insulin sensitivity. However, mice fed a SRHFD exhibited increased insulin content in the pancreas. Overall, while selenite protects against palmitate-induced insulin resistance in vitro, obesity impedes the effect of selenite on insulin action and adipose tissue metabolism in vivo.
KW  - selenite
KW  - insulin
KW  - adipose tissue
KW  - obesity
KW  - insulin resistance
Y1  - 2022
U6  - https://doi.org/10.3390/antiox11050862
SN  - 2076-3921
VL  - 11
SP  - 1
EP  - 16
PB  - MDPI
CY  - Basel, Schweiz
ET  - 5
ER  - 
TY  - GEN
A1  - Hauffe, Robert
A1  - Rath, Michaela
A1  - Agyapong, Wilson
A1  - Jonas, Wenke
A1  - Vogel, Heike
A1  - Schulz, Tim Julius
A1  - Schwarz, Maria
A1  - Kipp, Anna Patricia
A1  - Blüher, Matthias
A1  - Kleinridders, André
T1  - Obesity Hinders the Protective Effect of Selenite Supplementation on Insulin Signaling
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - The intake of high-fat diets (HFDs) containing large amounts of saturated long-chain fatty acids leads to obesity, oxidative stress, inflammation, and insulin resistance. The trace element selenium, as a crucial part of antioxidative selenoproteins, can protect against the development of diet-induced insulin resistance in white adipose tissue (WAT) by increasing glutathione peroxidase 3 (GPx3) and insulin receptor (IR) expression. Whether selenite (Se) can attenuate insulin resistance in established lipotoxic and obese conditions is unclear. We confirm that GPX3 mRNA expression in adipose tissue correlates with BMI in humans. Cultivating 3T3-L1 pre-adipocytes in palmitate-containing medium followed by Se treatment attenuates insulin resistance with enhanced GPx3 and IR expression and adipocyte differentiation. However, feeding obese mice a selenium-enriched high-fat diet (SRHFD) only resulted in a modest increase in overall selenoprotein gene expression in WAT in mice with unaltered body weight development, glucose tolerance, and insulin resistance. While Se supplementation improved adipocyte morphology, it did not alter WAT insulin sensitivity. However, mice fed a SRHFD exhibited increased insulin content in the pancreas. Overall, while selenite protects against palmitate-induced insulin resistance in vitro, obesity impedes the effect of selenite on insulin action and adipose tissue metabolism in vivo.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1267 
KW  - selenite
KW  - insulin
KW  - adipose tissue
KW  - obesity
KW  - insulin resistance
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-561709
SN  - 1866-8372
SP  - 1
EP  - 16
PB  - Universitätsverlag Potsdam
CY  - Potsdam
ER  - 
TY  - JOUR
A1  - 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  - 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  - 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  - Moehlig, M.
A1  - Floeter, A.
A1  - Spranger, Joachim
A1  - Weickert, Martin O.
A1  - Schill, T.
A1  - Schloesser, H. W.
A1  - Brabant, G.
A1  - Pfeiffer, Andreas F. H.
A1  - Selbig, Joachim
A1  - Schoefl, C.
T1  - Predicting impaired glucose metabolism in women with polycystic ovary syndrome by decision tree modelling
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - Aims/hypothesis Polycystic ovary syndrome (PCOS) is a risk factor of type 2 diabetes. Screening for impaired glucose metabolism (IGM) with an OGTT has been recommended, but this is relatively time-consuming and inconvenient. Thus, a strategy that could minimise the need for an OGTT would be beneficial. Materials and methods Consecutive PCOS patients (n=118) with fasting glucose < 6.1 mmol/l were included in the study. Parameters derived from medical history, clinical examination and fasting blood samples were assessed by decision tree modelling for their ability to discriminate women with IGM (2-h OGTT value >= 7.8 mmol/l) from those with NGT. Results According to the OGTT results, 93 PCOS women had NGT and 25 had IGM. The best decision tree consisted of HOMA-IR, the proinsulin:insulin ratio, proinsulin, 17-OH progesterone and the ratio of luteinising hormone:follicle-stimulating hormone. This tree identified 69 women with NGT. The remaining 49 women included all women with IGM (100% sensitivity, 74% specificity to detect IGM). Pruning this tree to three levels still identified 53 women with NGT (100% sensitivity, 57% specificity to detect IGM). Restricting the data matrix used for tree modelling to medical history and clinical parameters produced a tree using BMI, waist circumference and WHR. Pruning this tree to two levels separated 27 women with NGT (100% sensitivity, 29% specificity to detect IGM). The validity of both trees was tested by a leave-10%-out cross-validation. Conclusions/interpretation Decision trees are useful tools for separating PCOS women with NGT from those with IGM. They can be used for stratifying the metabolic screening of PCOS women, whereby the number of OGTTs can be markedly reduced.
KW  - decision tree
KW  - HOMA
KW  - impaired glucose tolerance
KW  - insulin
KW  - insulin resistance
KW  - polycystic ovary syndrome
KW  - proinsulin
KW  - type 2 diabetes mellitus
Y1  - 2006
U6  - https://doi.org/10.1007/s00125-006-0395-0
SN  - 0012-186X
VL  - 49
SP  - 2572
EP  - 2579
PB  - Springer
CY  - Berlin
ER  -