@phdthesis{GonzalezCamargo2016,
  author    = {Gonzalez Camargo, Rodolfo},
  title     = {Insulin resistance in cancer cachexia and metabolic syndrome},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-100973},
  school      = {Universit{\"a}t Potsdam},
  pages     = {104},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}
@phdthesis{Hauffe2021,
  author    = {Hauffe, Robert},
  title     = {Investigating metabolic consequences of an HSP60 reduction during diet-induced obesity},
  doi       = {10.25932/publishup-50929},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-509294},
  school      = {Universit{\"a}t Potsdam},
  pages     = {xxi, 116},
  year      = {2021},
  abstract  = {The mitochondrial chaperone complex HSP60/HSP10 facilitates mitochondrial protein homeostasis by folding more than 300 mitochondrial matrix proteins. It has been shown previously that HSP60 is downregulated in brains of type 2 diabetic (T2D) mice and patients, causing mitochondrial dysfunction and insulin resistance. As HSP60 is also decreased in peripheral tissues in T2D animals, this thesis investigated the effect of overall reduced HSP60 in the development of obesity and associated co-morbidities. To this end, both female and male C57Bl/6N control (i.e. without further alterations in their genome, Ctrl) and heterozygous whole-body Hsp60 knock-out (Hsp60+/-) mice, which exhibit a 50 \% reduction of HSP60 in all tissues, were fed a normal chow diet (NCD) or a highfat diet (HFD, 60 \% calories from fat) for 16 weeks and were subjected to extensive metabolic phenotyping including indirect calorimetry, NMR spectroscopy, insulin, glucose and pyruvate tolerance tests, vena cava insulin injections, as well as histological and molecular analysis. Interestingly, NCD feeding did not result in any striking phenotype, only a mild increase in energy expenditure in Hsp60+/- mice. Exposing mice to a HFD however revealed an increased body weight due to higher muscle mass in female Hsp60+/- mice, with a simultaneous decrease in energy expenditure. Additionally, these mice displayed decreased fasting glycemia. Opposingly, male Hsp60+/- compared to control mice showed lower body weight gain due to decreased fat mass and an increased energy expenditure, strikingly independent of lean mass. Further, only male Hsp60+/- mice display improved HOMA-IR and Matsuda insulin sensitivity indices. Despite the opposite phenotype in regards to body weight development, Hsp60+/- mice of both sexes show a significantly higher cell number, as well as a reduction in adipocyte size in the subcutaneous and gonadal white adipose tissue (sc/gWAT). Curiously, this adipocyte hyperplasia - usually associated with positive aspects of WAT function - is disconnected from metabolic improvements, as the gWAT of male Hsp60+/- mice shows mitochondrial dysfunction, oxidative stress, and insulin resistance. Transcriptomic analysis of gWAT shows an up regulation of genes involved in macroautophagy. Confirmatory, expression of microtubuleassociated protein 1A/1B light chain 3B (LC3), as a protein marker of autophagy, and direct measurement of lysosomal activity is increased in the gWAT of male Hsp60+/- mice. In summary, this thesis revealed a novel gene-nutrient interaction. The reduction of the crucial chaperone HSP60 did not have large effects in mice fed a NCD, but impacted metabolism during DIO in a sex-specific manner, where, despite opposing body weight and body composition phenotypes, both female and male Hsp60+/- mice show signs of protection from high fat diet-induced systemic insulin resistance.},
  language  = {en}
}
@phdthesis{ColemanMacGregorofInneregny,
  author    = {Coleman Mac Gregor of Inneregny, Charles Dominic},
  title     = {Rolle von mPGES1-abh{\"a}ngig gebildetem Prostaglandin E2 bei der Ausbildung von Insulinresistenz und nicht-alkoholischer Fettlebererkrankung durch die Modulation der Funktion von Lebermakrophagen},
  school      = {Universit{\"a}t Potsdam},
  pages     = {183},
  abstract  = {Eine St{\"o}rung des Leberstoffwechsels durch die Ausbildung einer Insulinresistenz kann zu Folgeerkrankungen wie der nicht alkoholischen Fettlebererkrankung (NAFLD) bis hin zur Steatohepatitis (NASH) und zur Entwicklung eines Diabetes Typ II f{\"u}hren. Am Krankheitsverlauf sind residente (Kupfferzellen) sowie infiltrierende Makrophagen beteiligt, die durch inflammatorische Stimuli aktiviert werden und zur Progression von Lebererkrankungen f{\"u}hren k{\"o}nnen. Im Rahmen dieser Arbeit wurde die Rolle von mPGES1-abh{\"a}ngig gebildetem Prostaglandin E2 (PGE2) an der Modulation von aktivierten Lebermakrophagen untersucht. Dazu wurden Kupfferzellen und Peritonealmakrophagen (als Modell f{\"u}r infiltrierende Makrophagen) aus Wildtyp und mPGES1-defizienten M{\"a}usen isoliert. Beide Makrophagen­populationen wurden in Zellkulturversuchen mit Lipopolysacchariden (LPS) aktiviert und auf ihre PGE2-Synthese, Genexpression und Sekretion von verschiedenen Cytokinen hin untersucht. Die beiden Makrophagenpopulationen unterschieden sich hinsichtlich der PGE2-Synthese bei mPGSE1-Defizienz. W{\"a}hrend bei Peritonealmakrophagen die LPS-abh{\"a}ngige PGE2-Synthese bei Abwesenheit der mPGES1 fast vollst{\"a}ndig reprimiert war, war bei Kupfferzellen nur eine 25\%ige Abnahme zu verzeichnen. Die postulierte selbstverst{\"a}rkende R{\"u}ckkopplungsschleife von PGE2 im Hinblick auf seine eigene Synthese konnte in isolierten Peritonealmakrophagen, nicht jedoch in Kupfferzellen, best{\"a}tigt werden. In Kupfferzellen f{\"u}hrte exogenes PGE2 ferner zu einer Repression von den pro-inflammatorischen Cytokinen TNFα und IL-1β und f{\"u}r endogenes PGE2 konnte in diesem Zelltyp kein Effekt festgestellt werden. In Peritonealmakrophagen konnte hingegen auch f{\"u}r endogenes PGE2 eine reprimierende Wirkung auf die Expression von TNFα beobachtet werden. Das ist eventuell auf eine h{\"o}here Sensitivit{\"a}t gegen{\"u}ber PGE2 von Peritonealmakrophagen im Vergleich zu Kupfferzellen zur{\"u}ckzuf{\"u}hren. PGE2 wirkte unter den gew{\"a}hlten Versuchsbedingungen in vitro somit eher anti-inflammatorisch. Cholesterolkristalle induzierten in Kupfferzellen die Expression der PGE2-synthetisierenden Enzyme und verschiedener pro-inflammatorische Cytokine. Sie k{\"o}nnten somit zu einer Progression von NAFL zu NASH beitragen. Die Daten aus dieser Arbeit deuten darauf hin, dass PGE2 im Rahmen von entz{\"u}ndlichen Leberver{\"a}nderungen eine eher protektive Wirkung im Hinblick auf die Progression von NAFLD und Insulinresistenz haben k{\"o}nnte.},
  language  = {de}
}