TY - JOUR A1 - Aga-Barfknecht, Heja A1 - Soultoukis, George A. A1 - Stadion, Mandy A1 - Garcia-Carrizo, Francisco A1 - Jähnert, Markus A1 - Gottmann, Pascal A1 - Vogel, Heike A1 - Schulz, Tim Julius A1 - Schürmann, Annette T1 - Distinct adipogenic and fibrogenic differentiation capacities of mesenchymal stromal cells from pancreas and white adipose tissue JF - International journal of molecular sciences N2 - 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. KW - MSCs KW - fatty pancreas KW - WAT KW - lineage commitment KW - transcriptomics KW - miRNAs Y1 - 2022 U6 - https://doi.org/10.3390/ijms23042108 SN - 1422-0067 VL - 23 IS - 4 PB - Molecular Diversity Preservation International CY - Basel ER - TY - JOUR A1 - Kehm, Richard A1 - Jähnert, Markus A1 - Deubel, Stefanie A1 - Flore, Tanina A1 - König, Jeannette A1 - Jung, Tobias A1 - Stadion, Mandy A1 - Jonas, Wenke A1 - Schürmann, Annette A1 - Grune, Tilman A1 - Höhn, Annika T1 - Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: role of thioredoxin-interacting protein (TXNIP) JF - Redox Biology N2 - Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetesprone NZO mice. KW - aging KW - redox homeostasis KW - metabolic stress KW - beta-cells KW - cell cycle KW - thioredoxin-interacting protein Y1 - 2020 U6 - https://doi.org/10.1016/j.redox.2020.101748 SN - 2213-2317 VL - 37 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Aga-Barfknecht, Heja A1 - Hallahan, Nicole A1 - Gottmann, Pascal A1 - Jähnert, Markus A1 - Osburg, Sophie A1 - Schulze, Gunnar A1 - Kamitz, Anne A1 - Arends, Danny A1 - Brockmann, Gudrun A1 - Schallschmidt, Tanja A1 - Lebek, Sandra A1 - Chadt, Alexandra A1 - Al-Hasani, Hadi A1 - Joost, Hans-Georg A1 - Schürmann, Annette A1 - Vogel, Heike T1 - Identification of novel potential type 2 diabetes genes mediating beta-cell loss and hyperglycemia using positional cloning JF - Frontiers in genetics N2 - 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. KW - type 2 diabetes KW - beta-cell loss KW - insulin KW - positional cloning KW - transcriptomics KW - haplotype Y1 - 2020 U6 - https://doi.org/10.3389/fgene.2020.567191 SN - 1664-8021 VL - 11 PB - Frontiers Media CY - Lausanne ER - TY - JOUR A1 - Hauffe, Robert A1 - Rath, Michaela A1 - Schell, Mareike A1 - Ritter, Katrin A1 - Kappert, Kai A1 - Deubel, Stefanie A1 - Ott, Christiane A1 - Jähnert, Markus A1 - Jonas, Wenke A1 - Schürmann, Annette A1 - Kleinridders, André T1 - HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue JF - Molecular Metabolism N2 - 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. KW - Mitochondria KW - Stress response KW - Obesity KW - Glucose homeostasis KW - Insulin resistance KW - Adipose tissue Y1 - 2021 U6 - https://doi.org/10.1016/j.molmet.2021.101276 SN - 2212-8778 VL - 53 SP - 1 EP - 14 PB - Elsevier CY - Amsterdam, Niederlande ER - TY - JOUR A1 - Vogel, Heike A1 - Kamitz, Anne A1 - Hallahan, Nicole A1 - Lebek, Sandra A1 - Schallschmidt, Tanja A1 - Jonas, Wenke A1 - Jähnert, Markus A1 - Gottmann, Pascal A1 - Zellner, Lisa A1 - Kanzleiter, Timo A1 - Damen, Mareike A1 - Altenhofen, Delsi A1 - Burkhardt, Ralph A1 - Renner, Simone A1 - Dahlhoff, Maik A1 - Wolf, Eckhard A1 - Müller, Timo Dirk A1 - Blüher, Matthias A1 - Joost, Hans-Georg A1 - Chadt, Alexandra A1 - Al-Hasani, Hadi A1 - Schürmann, Annette T1 - A collective diabetes cross in combination with a computational framework to dissect the genetics of human obesity and Type 2 diabetes JF - Human molecular genetics N2 - 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. Y1 - 2018 U6 - https://doi.org/10.1093/hmg/ddy217 SN - 0964-6906 SN - 1460-2083 VL - 27 IS - 17 SP - 3099 EP - 3112 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Wittenbecher, Clemens A1 - Ouni, Meriem A1 - Kuxhaus, Olga A1 - Jähnert, Markus A1 - Gottmann, Pascal A1 - Teichmann, Andrea A1 - Meidtner, Karina A1 - Kriebel, Jennifer A1 - Grallert, Harald A1 - Pischon, Tobias A1 - Boeing, Heiner A1 - Schulze, Matthias Bernd A1 - Schürmann, Annette T1 - Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) and the Risk of Developing Type 2 Diabetes JF - Diabetes : a journal of the American Diabetes Association N2 - Recent studies suggest that insulin-like growth factor binding protein 2 (IGFBP-2) may protect against type 2 diabetes, but population-based human studies are scarce. We aimed to investigate the prospective association of circulating IGFBP-2 concentrations and of differential methylation in the IGFBP-2 gene with type 2 diabetes risk. Y1 - 2019 U6 - https://doi.org/10.2337/db18-0620 SN - 0012-1797 SN - 1939-327X VL - 68 IS - 1 SP - 188 EP - 197 PB - American Diabetes Association CY - Alexandria ER - TY - JOUR A1 - Kluth, Oliver A1 - Stadion, Mandy A1 - Gottmann, Pascal A1 - Aga-Barfknecht, Heja A1 - Jähnert, Markus A1 - Scherneck, Stephan A1 - Vogel, Heike A1 - Krus, Ulrika A1 - Seelig, Anett A1 - Ling, Charlotte A1 - Gerdes, Jantje A1 - Schürmann, Annette T1 - Decreased expression of cilia genes in pancreatic islets as a risk factor for type 2 diabetes in mice and humans JF - Cell reports N2 - 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. Y1 - 2019 U6 - https://doi.org/10.1016/j.celrep.2019.02.056 SN - 2211-1247 VL - 26 IS - 11 SP - 3027 EP - 3036 PB - Cell Press CY - Maryland Heights ER - TY - JOUR A1 - Gohlke, Sabrina A1 - Zagoriy, Vyacheslav A1 - Inostroza, Alvaro Cuadros A1 - Meret, Michael A1 - Mancini, Carola A1 - Japtok, Lukasz A1 - Schumacher, Fabian A1 - Kuhlow, Doreen A1 - Graja, Antonia A1 - Stephanowitz, Heike A1 - Jähnert, Markus A1 - Krause, Eberhard A1 - Wernitz, Andreas A1 - Petzke, Klaus-Juergen A1 - Schürmann, Annette A1 - Kleuser, Burkhard A1 - Schulz, Tim Julius T1 - Identification of functional lipid metabolism biomarkers of brown adipose tissue aging JF - Molecular Metabolism N2 - 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. KW - Brown adipose tissue KW - Aging KW - Ceramides KW - Sphingolipids KW - Dolichol lipids Y1 - 2019 U6 - https://doi.org/10.1016/j.molmet.2019.03.011 SN - 2212-8778 VL - 24 SP - 1 EP - 17 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Gancheva, Sofiya A1 - Ouni, Meriem A1 - Jelenik, Tomas A1 - Koliaki, Chrysi A1 - Szendroedi, Julia A1 - Toledo, Frederico G. S. A1 - Markgraf, Daniel Frank A1 - Pesta, Dominik H. A1 - Mastrototaro, Lucia A1 - De Filippo, Elisabetta A1 - Herder, Christian A1 - Jähnert, Markus A1 - Weiss, Jürgen A1 - Strassburger, Klaus A1 - Schlensak, Matthias A1 - Schürmann, Annette A1 - Roden, Michael T1 - Dynamic changes of muscle insulin sensitivity after metabolic surgery JF - Nature Communications N2 - 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. Y1 - 2019 U6 - https://doi.org/10.1038/s41467-019-12081-0 SN - 2041-1723 VL - 10 PB - Nature Publ. Group CY - London ER -