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 - Jonas, Wenke A1 - Kluth, Oliver A1 - Helms, Anett A1 - Voss, Sarah A1 - Jahnert, Markus A1 - Gottmann, Pascal A1 - Speckmann, Thilo A1 - Knebel, Birgit A1 - Chadt, Alexandra A1 - Al-Hasani, Hadi A1 - Schürmann, Annette A1 - Vogel, Heike T1 - Identification of novel genes involved in hyperglycemia in mice JF - International journal of molecular sciences N2 - Current attempts to prevent and manage type 2 diabetes have been moderately effective, and a better understanding of the molecular roots of this complex disease is important to develop more successful and precise treatment options. Recently, we initiated the collective diabetes cross, where four mouse inbred strains differing in their diabetes susceptibility were crossed with the obese and diabetes-prone NZO strain and identified the quantitative trait loci (QTL) Nidd13/NZO, a genomic region on chromosome 13 that correlates with hyperglycemia in NZO allele carriers compared to B6 controls. Subsequent analysis of the critical region, harboring 644 genes, included expression studies in pancreatic islets of congenic Nidd13/NZO mice, integration of single-cell data from parental NZO and B6 islets as well as haplotype analysis. Finally, of the five genes (Acot12, S100z, Ankrd55, Rnf180, and Iqgap2) within the polymorphic haplotype block that are differently expressed in islets of B6 compared to NZO mice, we identified the calcium-binding protein S100z gene to affect islet cell proliferation as well as apoptosis when overexpressed in MINE cells. In summary, we define S100z as the most striking gene to be causal for the diabetes QTL Nidd13/NZO by affecting beta-cell proliferation and apoptosis. Thus, S100z is an entirely novel diabetes gene regulating islet cell function. KW - beta-cell KW - diabetes KW - proliferation KW - apoptosis KW - QTL Y1 - 2022 U6 - https://doi.org/10.3390/ijms23063205 SN - 1661-6596 SN - 1422-0067 VL - 23 IS - 6 PB - MDPI CY - Basel ER - TY - JOUR A1 - Delpero, Manuel A1 - Arends, Danny A1 - Sprechert, Maximilian A1 - Krause, Florian A1 - Kluth, Oliver A1 - Schürmann, Annette A1 - Brockmann, Gudrun A. A1 - Hesse, Deike T1 - Identification of four novel QTL linked to the metabolic syndrome in the Berlin Fat Mouse JF - International journal of obesity / North American Association for the Study of Obesity N2 - 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. Y1 - 2022 U6 - https://doi.org/10.1038/s41366-021-00991-3 SN - 0307-0565 SN - 1476-5497 VL - 46 IS - 2 SP - 307 EP - 315 PB - Nature Publ. Group CY - Avenel, NJ ER -