TY - JOUR A1 - John, Cathleen A1 - Grune, Jana A1 - Ott, Christiane A1 - Nowotny, Kerstin A1 - Deubel, Stefanie A1 - Kühne, Arne A1 - Schubert, Carola A1 - Kintscher, Ulrich A1 - Regitz-Zagrosek, Vera A1 - Grune, Tilman T1 - Sex Differences in Cardiac Mitochondria in the New Zealand Obese Mouse JF - Frontiers in Endocrinology N2 - Background: Obesity is a risk factor for diseases including type 2 diabetes mellitus (T2DM) and cardiovascular disorders. Diabetes itself contributes to cardiac damage. Thus, studying cardiovascular events and establishing therapeutic intervention in the period of type T2DM onset and manifestation are of highest importance. Mitochondrial dysfunction is one of the pathophysiological mechanisms leading to impaired cardiac function. Methods: An adequate animal model for studying pathophysiology of T2DM is the New Zealand Obese (NZO) mouse. These mice were maintained on a high-fat diet (HFD) without carbohydrates for 13 weeks followed by 4 week HFD with carbohydrates. NZO mice developed severe obesity and only male mice developed manifest T2DM. We determined cardiac phenotypes and mitochondrial function as well as cardiomyocyte signaling in this model. Results: The development of an obese phenotype and T2DM in male mice was accompanied by an impaired systolic function as judged by echocardiography and MyH6/7 expression. Moreover, the mitochondrial function only in male NZO hearts was significantly reduced and ERK1/2 and AMPK protein levels were altered. Conclusions: This is the first report demonstrating that the cardiac phenotype in male diabetic NZO mice is associated with impaired cardiac energy function and signaling events. KW - NZO KW - heart KW - obesity KW - mitochondrial function KW - echocardiography KW - systolic function Y1 - 2018 U6 - https://doi.org/10.3389/fendo.2018.00732 SN - 1664-2392 VL - 9 PB - Frontiers Research Foundation CY - Lausanne ER - TY - JOUR A1 - Li, Chen A1 - Stoma, Svetlana A1 - Lotta, Luca A. A1 - Warner, Sophie A1 - Albrecht, Eva A1 - Allione, Alessandra A1 - Arp, Pascal P. A1 - Broer, Linda A1 - Buxton, Jessica L. A1 - Boeing, Heiner A1 - Langenberg, Claudia A1 - Codd, Veryan T1 - Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length JF - American Journal of Human Genetics N2 - Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease. KW - Mendelian randomization KW - risk KW - variants KW - disease KW - cancer KW - loci KW - database KW - genes KW - heart KW - gwas Y1 - 2019 VL - 106 IS - 3 PB - Elsevier CY - Amsterdam ER - TY - GEN A1 - Li, Chen A1 - Stoma, Svetlana A1 - Lotta, Luca A. A1 - Warner, Sophie A1 - Albrecht, Eva A1 - Allione, Alessandra A1 - Arp, Pascal P. A1 - Broer, Linda A1 - Buxton, Jessica L. A1 - Boeing, Heiner A1 - Langenberg, Claudia A1 - Codd, Veryan T1 - Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1205 KW - Mendelian randomization KW - risk KW - variants KW - disease KW - cancer KW - loci KW - database KW - genes KW - heart KW - gwas Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-526843 SN - 1866-8372 IS - 3 ER -