@article{VogelKamitzHallahanetal.2018,
  author    = {Vogel, Heike and Kamitz, Anne and Hallahan, Nicole and Lebek, Sandra and Schallschmidt, Tanja and Jonas, Wenke and J{\"a}hnert, Markus and Gottmann, Pascal and Zellner, Lisa and Kanzleiter, Timo and Damen, Mareike and Altenhofen, Delsi and Burkhardt, Ralph and Renner, Simone and Dahlhoff, Maik and Wolf, Eckhard and M{\"u}ller, Timo Dirk and Bl{\"u}her, Matthias and Joost, Hans-Georg and Chadt, Alexandra and Al-Hasani, Hadi and Sch{\"u}rmann, Annette},
  title     = {A collective diabetes cross in combination with a computational framework to dissect the genetics of human obesity and Type 2 diabetes},
  series = {Human molecular genetics},
  volume    = {27},
  journal   = {Human molecular genetics},
  number    = {17},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {0964-6906},
  doi       = {10.1093/hmg/ddy217},
  pages     = {3099 -- 3112},
  year      = {2018},
  abstract  = {To explore the genetic determinants of obesity and Type 2 diabetes (T2D), the German Center for Diabetes Research (DZD) conducted crossbreedings of the obese and diabetes-prone New Zealand Obese mouse strain with four different lean strains (B6, DBA, C3H, 129P2) that vary in their susceptibility to develop T2D. Genome-wide linkage analyses localized more than 290 quantitative trait loci (QTL) for obesity, 190 QTL for diabetes-related traits and 100 QTL for plasma metabolites in the out-cross populations. A computational framework was developed that allowed to refine critical regions and to nominate a small number of candidate genes by integrating reciprocal haplotype mapping and transcriptome data. The efficiency of the complex procedure was demonstrated for one obesity QTL. The genomic interval of 35 Mb with 502 annotated candidate genes was narrowed down to six candidates. Accordingly, congenic mice retained the obesity phenotype owing to an interval that contains three of the six candidate genes. Among these the phospholipase PLA2G4A exhibited an elevated expression in adipose tissue of obese human subjects and is therefore a critical regulator of the obesity locus. Together, our broad and complex approach demonstrates that combined- and comparative-cross analysis exhibits improved mapping resolution and represents a valid tool for the identification of disease genes.},
  language  = {en}
}
@misc{VolckmarHanPuetteretal.2016,
  author    = {Volckmar, Anna-Lena and Han, Chung-Ting and P{\"u}tter, Carolin and Haas, Stefan and Vogel, Carla I. G. and Knoll, Nadja and Struve, Christoph and G{\"o}bel, Maria and Haas, Katharina and Herrfurth, Nikolas and Jarick, Ivonne and Grallert, Harald and Sch{\"u}rmann, Annette and Al- Hasani, Hadi and Hebebrand, Johannes and Sauer, Sascha and Hinney, Anke},
  title     = {Analysis of genes involved in body weight regulation by targeted re-sequencing},
  series = {PLoS ONE},
  journal   = {PLoS ONE},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-410289},
  pages     = {16},
  year      = {2016},
  abstract  = {Introduction Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing. Methods We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) >= 99th percentile and 176 lean adults (BMI <= 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults. Results and Conclusion We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (p(TDT) = 0.03 in 705 trios). Eleven of the variants were rare, thus were only detected heterozygously in up to ten individual(s) of the complete screening sample of 372 individuals. Two of them (in FTO and MSRA) were found in lean individuals, nine in extremely obese. In silico analyses of the 11 variants did not reveal functional implications for the mutations. Concordant with our hypothesis we detected a rare variant that potentially leads to loss of FTO function in a lean individual. For TBC1D1, in contrary to our hypothesis, the loss of function variant (Arg443Stop) was found in an obese individual. Functional in vitro studies are warranted.},
  language  = {en}
}
@misc{HenkelColemanMacGregorofInneregnySchraplauetal.2018,
  author    = {Henkel, Janin and Coleman Mac Gregor of Inneregny, Charles Dominic and Schraplau, Anne and J{\"o}hrens, Korinna and Weiss, Thomas Siegfried and Jonas, Wenke and Sch{\"u}rmann, Annette and P{\"u}schel, Gerhard Paul},
  title     = {Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {483},
  issn      = {1866-8372},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-420879},
  pages     = {11},
  year      = {2018},
  abstract  = {In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.},
  language  = {en}
}
@article{HenkelColemanMacGregorofInneregnySchraplauetal.2018,
  author    = {Henkel, Janin and Coleman Mac Gregor of Inneregny, Charles Dominic and Schraplau, Anne and J{\"o}hrens, Korinna and Weiss, Thomas Siegfried and Jonas, Wenke and Sch{\"u}rmann, Annette and P{\"u}schel, Gerhard Paul},
  title     = {Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model},
  series = {Scientific Reports},
  journal   = {Scientific Reports},
  number    = {8},
  publisher = {Nature Research},
  address   = {London},
  issn      = {2045-2322},
  doi       = {10.1038/s41598-018-34633-y},
  pages     = {1 -- 11},
  year      = {2018},
  abstract  = {In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.},
  language  = {en}
}
@article{HenkelColemanSchraplauetal.2018,
  author    = {Henkel, Janin and Coleman, Charles Dominic and Schraplau, Anne and Joehrens, Korinna and Weiss, Thomas Siegfried and Jonas, Wenke and Sch{\"u}rmann, Annette and P{\"u}schel, Gerhard Paul},
  title     = {Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model},
  series = {Scientific reports},
  volume    = {8},
  journal   = {Scientific reports},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2045-2322},
  doi       = {10.1038/s41598-018-34633-y},
  pages     = {11},
  year      = {2018},
  abstract  = {In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.},
  language  = {en}
}
@misc{WardelmannRathCastroetal.2021,
  author    = {Wardelmann, Kristina and Rath, Michaela and Castro, Jos{\´e} Pedro and Bl{\"u}mel, Sabine and Schell, Mareike and Hauffe, Robert and Schumacher, Fabian and Flore, Tanina and Ritter, Katrin and Wernitz, Andreas and Hosoi, Toru and Ozawa, Koichiro and Kleuser, Burkhard and Weiß, J{\"u}rgen and Sch{\"u}rmann, Annette and Kleinridders, Andr{\´e}},
  title     = {Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {5},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-52298},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-522985},
  pages     = {24},
  year      = {2021},
  abstract  = {Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.},
  language  = {en}
}
@article{WardelmannRathCastroetal.2021,
  author    = {Wardelmann, Kristina and Rath, Michaela and Castro, Jos{\´e} Pedro and Bl{\"u}mel, Sabine and Schell, Mareike and Hauffe, Robert and Schumacher, Fabian and Flore, Tanina and Ritter, Katrin and Wernitz, Andreas and Hosoi, Toru and Ozawa, Koichiro and Kleuser, Burkhard and Weiß, J{\"u}rgen and Sch{\"u}rmann, Annette and Kleinridders, Andr{\´e}},
  title     = {Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus},
  series = {Antioxidants},
  volume    = {10},
  journal   = {Antioxidants},
  number    = {5},
  publisher = {MDPI},
  address   = {Basel},
  issn      = {2076-3921},
  doi       = {10.3390/antiox10050711},
  pages     = {22},
  year      = {2021},
  abstract  = {Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.},
  language  = {en}
}
@article{KluthStadionGottmannetal.2019,
  author    = {Kluth, Oliver and Stadion, Mandy and Gottmann, Pascal and Aga-Barfknecht, Heja and J{\"a}hnert, Markus and Scherneck, Stephan and Vogel, Heike and Krus, Ulrika and Seelig, Anett and Ling, Charlotte and Gerdes, Jantje and Sch{\"u}rmann, Annette},
  title     = {Decreased expression of cilia genes in pancreatic islets as a risk factor for type 2 diabetes in mice and humans},
  series = {Cell reports},
  volume    = {26},
  journal   = {Cell reports},
  number    = {11},
  publisher = {Cell Press},
  address   = {Maryland Heights},
  issn      = {2211-1247},
  doi       = {10.1016/j.celrep.2019.02.056},
  pages     = {3027 -- 3036},
  year      = {2019},
  abstract  = {An insufficient adaptive beta-cell compensation is a hallmark of type 2 diabetes (T2D). Primary cilia function as versatile sensory antennae regulating various cellular processes, but their role on compensatory beta-cell replication has not been examined. Here, we identify a significant enrichment of downregulated, cilia-annotated genes in pancreatic islets of diabetes-prone NZO mice as compared with diabetes-resistant B6-ob/ob mice. Among 327 differentially expressed mouse cilia genes, 81 human orthologs are also affected in islets of diabetic donors. Islets of nondiabetic mice and humans show a substantial overlap of upregulated cilia genes that are linked to cell-cycle progression. The shRNA-mediated suppression of KIF3A, essential for ciliogenesis, impairs division of MINE beta cells as well as in dispersed primary mouse and human islet cells, as shown by decreased BrdU incorporation. These findings demonstrate the substantial role of cilia-gene regulation on islet function and T2D risk.},
  language  = {en}
}
@article{LaegerCastanoMartinezWernoetal.2018,
  author    = {Laeger, Thomas and Castano-Martinez, Teresa and Werno, Martin W. and Japtok, Lukasz and Baumeier, Christian and Jonas, Wenke and Kleuser, Burkhard and Sch{\"u}rmann, Annette},
  title     = {Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes},
  series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  volume    = {61},
  journal   = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  number    = {6},
  publisher = {Springer},
  address   = {New York},
  issn      = {0012-186X},
  doi       = {10.1007/s00125-018-4595-1},
  pages     = {1459 -- 1469},
  year      = {2018},
  abstract  = {Aims/hypothesis Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. Methods We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ\%; CON) or low (4 kJ\%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Results Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Conclusion/interpretation Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se.},
  language  = {en}
}
@article{AgaBarfknechtSoultoukisStadionetal.2022,
  author    = {Aga-Barfknecht, Heja and Soultoukis, George A. and Stadion, Mandy and Garcia-Carrizo, Francisco and J{\"a}hnert, Markus and Gottmann, Pascal and Vogel, Heike and Schulz, Tim Julius and Sch{\"u}rmann, Annette},
  title     = {Distinct adipogenic and fibrogenic differentiation capacities of mesenchymal stromal cells from pancreas and white adipose tissue},
  series = {International journal of molecular sciences},
  volume    = {23},
  journal   = {International journal of molecular sciences},
  number    = {4},
  publisher = {Molecular Diversity Preservation International},
  address   = {Basel},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23042108},
  pages     = {21},
  year      = {2022},
  abstract  = {Pancreatic steatosis associates with beta-cell failure and may participate in the development of type-2-diabetes. Our previous studies have shown that diabetes-susceptible mice accumulate more adipocytes in the pancreas than diabetes-resistant mice. In addition, we have demonstrated that the co-culture of pancreatic islets and adipocytes affect insulin secretion. The aim of this current study was to elucidate if and to what extent pancreas-resident mesenchymal stromal cells (MSCs) with adipogenic progenitor potential differ from the corresponding stromal-type cells of the inguinal white adipose tissue (iWAT). miRNA (miRNome) and mRNA expression (transcriptome) analyses of MSCs isolated by flow cytometry of both tissues revealed 121 differentially expressed miRNAs and 1227 differentially expressed genes (DEGs). Target prediction analysis estimated 510 DEGs to be regulated by 58 differentially expressed miRNAs. Pathway analyses of DEGs and miRNA target genes showed unique transcriptional and miRNA signatures in pancreas (pMSCs) and iWAT MSCs (iwatMSCs), for instance fibrogenic and adipogenic differentiation, respectively. Accordingly, iwatMSCs revealed a higher adipogenic lineage commitment, whereas pMSCs showed an elevated fibrogenesis. As a low degree of adipogenesis was also observed in pMSCs of diabetes-susceptible mice, we conclude that the development of pancreatic steatosis has to be induced by other factors not related to cell-autonomous transcriptomic changes and miRNA-based signals.},
  language  = {en}
}