@article{AgaBarfknechtHallahanGottmannetal.2020,
  author    = {Aga-Barfknecht, Heja and Hallahan, Nicole and Gottmann, Pascal and J{\"a}hnert, Markus and Osburg, Sophie and Schulze, Gunnar and Kamitz, Anne and Arends, Danny and Brockmann, Gudrun and Schallschmidt, Tanja and Lebek, Sandra and Chadt, Alexandra and Al-Hasani, Hadi and Joost, Hans-Georg and Sch{\"u}rmann, Annette and Vogel, Heike},
  title     = {Identification of novel potential type 2 diabetes genes mediating beta-cell loss and hyperglycemia using positional cloning},
  series = {Frontiers in genetics},
  volume    = {11},
  journal   = {Frontiers in genetics},
  publisher = {Frontiers Media},
  address   = {Lausanne},
  issn      = {1664-8021},
  doi       = {10.3389/fgene.2020.567191},
  pages     = {11},
  year      = {2020},
  abstract  = {Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL),Nidd/DBAon chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of beta-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four (Kti12,Osbpl9,Ttc39a, andCalr4) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTLNidd/DBA. Future studies are necessary to understand the exact role of the different candidates in beta-cell function and their contribution in maintaining glycemic control.},
  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}
}
@article{CastanoMartinezSchumacherSchumacheretal.2019,
  author    = {Casta{\~n}o Mart{\´i}nez, Mar{\´i}a Teresa and Schumacher, Fabian and Schumacher, Silke and Kochlik, Bastian Max and Weber, Daniela and Grune, Tilman and Biemann, Ronald and McCann, Adrian and Abraham, Klaus and Weikert, Cornelia and Kleuse, Burkhard and Sch{\"u}rmann, Annette and Laeger, Thomas},
  title     = {Methionine restriction prevents onset of type 2 diabetes in NZO mice},
  series = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology},
  volume    = {33},
  journal   = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology},
  number    = {6},
  publisher = {Federation of American Societies for Experimental Biology},
  address   = {Bethesda},
  issn      = {0892-6638},
  doi       = {10.1096/fj.201900150R},
  pages     = {7092 -- 7102},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}
@article{DelperoArendsSprechertetal.2022,
  author    = {Delpero, Manuel and Arends, Danny and Sprechert, Maximilian and Krause, Florian and Kluth, Oliver and Sch{\"u}rmann, Annette and Brockmann, Gudrun A. and Hesse, Deike},
  title     = {Identification of four novel QTL linked to the metabolic syndrome in the Berlin Fat Mouse},
  series = {International journal of obesity / North American Association for the Study of Obesity},
  volume    = {46},
  journal   = {International journal of obesity / North American Association for the Study of Obesity},
  number    = {2},
  publisher = {Nature Publ. Group},
  address   = {Avenel, NJ},
  issn      = {0307-0565},
  doi       = {10.1038/s41366-021-00991-3},
  pages     = {307 -- 315},
  year      = {2022},
  abstract  = {Background The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and the metabolic syndrome. This study aimed to identify genetic variants associated with impaired glucose metabolism using the obese lines BFMI861-S1 and BFMI861-S2, which are genetically closely related, but differ in several traits. BFMI861-S1 is insulin resistant and stores ectopic fat in the liver, whereas BFMI861-S2 is insulin sensitive. Methods In generation 10, 397 males of an advanced intercross line (AIL) BFMI861-S1 x BFMI861-S2 were challenged with a high-fat, high-carbohydrate diet and phenotyped over 25 weeks. QTL-analysis was performed after selective genotyping of 200 mice using the GigaMUGA Genotyping Array. Additional 197 males were genotyped for 7 top SNPs in QTL regions. For the prioritization of positional candidate genes whole genome sequencing and gene expression data of the parental lines were used. Results Overlapping QTL for gonadal adipose tissue weight and blood glucose concentration were detected on chromosome (Chr) 3 (95.8-100.1 Mb), and for gonadal adipose tissue weight, liver weight, and blood glucose concentration on Chr 17 (9.5-26.1 Mb). Causal modeling suggested for Chr 3-QTL direct effects on adipose tissue weight, but indirect effects on blood glucose concentration. Direct effects on adipose tissue weight, liver weight, and blood glucose concentration were suggested for Chr 17-QTL. Prioritized positional candidate genes for the identified QTL were Notch2 and Fmo5 (Chr 3) and Plg and Acat2 (Chr 17). Two additional QTL were detected for gonadal adipose tissue weight on Chr 15 (67.9-74.6 Mb) and for body weight on Chr 16 (3.9-21.4 Mb). Conclusions QTL mapping together with a detailed prioritization approach allowed us to identify candidate genes associated with traits of the metabolic syndrome. In addition, we provided evidence for direct and indirect genetic effects on blood glucose concentration in the insulin-resistant mouse line BFMI861-S1.},
  language  = {en}
}
@article{GanchevaOuniJeleniketal.2019,
  author    = {Gancheva, Sofiya and Ouni, Meriem and Jelenik, Tomas and Koliaki, Chrysi and Szendroedi, Julia and Toledo, Frederico G. S. and Markgraf, Daniel Frank and Pesta, Dominik H. and Mastrototaro, Lucia and De Filippo, Elisabetta and Herder, Christian and J{\"a}hnert, Markus and Weiss, J{\"u}rgen and Strassburger, Klaus and Schlensak, Matthias and Sch{\"u}rmann, Annette and Roden, Michael},
  title     = {Dynamic changes of muscle insulin sensitivity after metabolic surgery},
  series = {Nature Communications},
  volume    = {10},
  journal   = {Nature Communications},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2041-1723},
  doi       = {10.1038/s41467-019-12081-0},
  pages     = {13},
  year      = {2019},
  abstract  = {The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. We monitored skeletal muscle metabolism in obese individuals before and over 52 weeks after metabolic surgery. Initial weight loss occurs in parallel with a decrease in muscle oxidative capacity and respiratory control ratio. Persistent elevation of intramyocellular lipid intermediates, likely resulting from unrestrained adipose tissue lipolysis, accompanies the lack of rapid changes in insulin sensitivity. Simultaneously, alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function associate with subsequent distinct DNA methylation patterns at 52 weeks after surgery. Thus, initial unfavorable metabolic changes including insulin resistance of adipose tissue and skeletal muscle precede epigenetic modifications of genes involved in muscle energy metabolism and the long-term improvement of insulin sensitivity.},
  language  = {en}
}
@article{GohlkeZagoriyInostrozaetal.2019,
  author    = {Gohlke, Sabrina and Zagoriy, Vyacheslav and Inostroza, Alvaro Cuadros and Meret, Michael and Mancini, Carola and Japtok, Lukasz and Schumacher, Fabian and Kuhlow, Doreen and Graja, Antonia and Stephanowitz, Heike and J{\"a}hnert, Markus and Krause, Eberhard and Wernitz, Andreas and Petzke, Klaus-Juergen and Sch{\"u}rmann, Annette and Kleuser, Burkhard and Schulz, Tim Julius},
  title     = {Identification of functional lipid metabolism biomarkers of brown adipose tissue aging},
  series = {Molecular Metabolism},
  volume    = {24},
  journal   = {Molecular Metabolism},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {2212-8778},
  doi       = {10.1016/j.molmet.2019.03.011},
  pages     = {1 -- 17},
  year      = {2019},
  abstract  = {Objective: Aging is accompanied by loss of brown adipocytes and a decline in their thermogenic potential, which may exacerbate the development of adiposity and other metabolic disorders. Presently, only limited evidence exists describing the molecular alterations leading to impaired brown adipogenesis with aging and the contribution of these processes to changes of systemic energy metabolism. Methods: Samples of young and aged murine brown and white adipose tissue were used to compare age-related changes of brown adipogenic gene expression and thermogenesis-related lipid mobilization. To identify potential markers of brown adipose tissue aging, non-targeted proteomic and metabolomic as well as targeted lipid analyses were conducted on young and aged tissue samples. Subsequently, the effects of several candidate lipid classes on brown adipocyte function were examined. Results: Corroborating previous reports of reduced expression of uncoupling protein-1, we observe impaired signaling required for lipid mobilization in aged brown fat after adrenergic stimulation. Omics analyses additionally confirm the age-related impairment of lipid homeostasis and reveal the accumulation of specific lipid classes, including certain sphingolipids, ceramides, and dolichols in aged brown fat. While ceramides as well as enzymes of dolichol metabolism inhibit brown adipogenesis, inhibition of sphingosine 1-phosphate receptor 2 induces brown adipocyte differentiation. Conclusions: Our functional analyses show that changes in specific lipid species, as observed during aging, may contribute to reduced thermogenic potential. They thus uncover potential biomarkers of aging as well as molecular mechanisms that could contribute to the degradation of brown adipocytes, thereby providing potential treatment strategies of age-related metabolic conditions.},
  language  = {en}
}
@article{GrajaGarciaCarrizoJanketal.2018,
  author    = {Graja, Antonia and Garcia-Carrizo, Francisco and Jank, Anne-Marie and Gohlke, Sabrina and Ambrosi, Thomas H. and Jonas, Wenke and Ussar, Siegfried and Kern, Matthias and Sch{\"u}rmann, Annette and Aleksandrova, Krasimira and Bluher, Matthias and Schulz, Tim Julius},
  title     = {Loss of periostin occurs in aging adipose tissue of mice and its genetic ablation impairs adipose tissue lipid metabolism},
  series = {Aging Cell},
  volume    = {17},
  journal   = {Aging Cell},
  number    = {5},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {1474-9718},
  doi       = {10.1111/acel.12810},
  pages     = {13},
  year      = {2018},
  abstract  = {Remodeling of the extracellular matrix is a key component of the metabolic adaptations of adipose tissue in response to dietary and physiological challenges. Disruption of its integrity is a well-known aspect of adipose tissue dysfunction, for instance, during aging and obesity. Adipocyte regeneration from a tissue-resident pool of mesenchymal stem cells is part of normal tissue homeostasis. Among the pathophysiological consequences of adipogenic stem cell aging, characteristic changes in the secretory phenotype, which includes matrix-modifying proteins, have been described. Here, we show that the expression of the matricellular protein periostin, a component of the extracellular matrix produced and secreted by adipose tissue-resident interstitial cells, is markedly decreased in aged brown and white adipose tissue depots. Using a mouse model, we demonstrate that the adaptation of adipose tissue to adrenergic stimulation and high-fat diet feeding is impaired in animals with systemic ablation of the gene encoding for periostin. Our data suggest that loss of periostin attenuates lipid metabolism in adipose tissue, thus recapitulating one aspect of age-related metabolic dysfunction. In human white adipose tissue, periostin expression showed an unexpected positive correlation with age of study participants. This correlation, however, was no longer evident after adjusting for BMI or plasma lipid and liver function biomarkers. These findings taken together suggest that age-related alterations of the adipose tissue extracellular matrix may contribute to the development of metabolic disease by negatively affecting nutrient homeostasis.},
  language  = {en}
}
@misc{HauffeRathSchelletal.2022,
  author    = {Hauffe, Robert and Rath, Michaela and Schell, Mareike and Ritter, Katrin and Kappert, Kai and Deubel, Stefanie and Ott, Christiane and J{\"a}hnert, Markus and Jonas, Wenke and Sch{\"u}rmann, Annette and Kleinridders, Andr{\´e}},
  title     = {HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue},
  series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  publisher = {Universit{\"a}tsverlag Potsdam},
  address   = {Potsdam},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-54800},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-548002},
  pages     = {1 -- 14},
  year      = {2022},
  abstract  = {Objective Insulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance. Methods Control and heterozygous whole-body HSP60 knockout (Hsp60+/-) mice were fed a high-fat diet (HFD, 60\% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis. Results Male Hsp60+/- mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60+/- mice in a glucose tolerance test. However, Hsp60+/- mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance. Conclusions We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance.},
  language  = {en}
}
@article{HauffeRathSchelletal.2021,
  author    = {Hauffe, Robert and Rath, Michaela and Schell, Mareike and Ritter, Katrin and Kappert, Kai and Deubel, Stefanie and Ott, Christiane and J{\"a}hnert, Markus and Jonas, Wenke and Sch{\"u}rmann, Annette and Kleinridders, Andr{\´e}},
  title     = {HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue},
  series = {Molecular Metabolism},
  volume    = {53},
  journal   = {Molecular Metabolism},
  publisher = {Elsevier},
  address   = {Amsterdam, Niederlande},
  issn      = {2212-8778},
  doi       = {10.1016/j.molmet.2021.101276},
  pages     = {1 -- 14},
  year      = {2021},
  abstract  = {Objective Insulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance. Methods Control and heterozygous whole-body HSP60 knockout (Hsp60+/-) mice were fed a high-fat diet (HFD, 60\% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis. Results Male Hsp60+/- mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60+/- mice in a glucose tolerance test. However, Hsp60+/- mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance. Conclusions We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance.},
  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}
}