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 - Keller, Johannes A1 - Catala-Lehnen, Philip A1 - Huebner, Antje K. A1 - Jeschke, Anke A1 - Heckt, Timo A1 - Lueth, Anja A1 - Krause, Matthias A1 - Koehne, Till A1 - Albers, Joachim A1 - Schulze, Jochen A1 - Schilling, Sarah A1 - Haberland, Michael A1 - Denninger, Hannah A1 - Neven, Mona A1 - Hermans-Borgmeyer, Irm A1 - Streichert, Thomas A1 - Breer, Stefan A1 - Barvencik, Florian A1 - Levkau, Bodo A1 - Rathkolb, Birgit A1 - Wolf, Eckhard A1 - Calzada-Wack, Julia A1 - Neff, Frauke A1 - Gailus-Durner, Valerie A1 - Fuchs, Helmut A1 - de Angelis, Martin Hrabe A1 - Klutmann, Susanne A1 - Tsourdi, Elena A1 - Hofbauer, Lorenz C. A1 - Kleuser, Burkhard A1 - Chun, Jerold A1 - Schinke, Thorsten A1 - Amling, Michael T1 - Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts JF - Nature Communications N2 - The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P(3). Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P(3)-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. Y1 - 2014 U6 - https://doi.org/10.1038/ncomms6215 SN - 2041-1723 VL - 5 PB - Nature Publ. Group CY - London ER -