44 results on '"Champy MF"'
Search Results
2. Analysis of the Bromo Adjacent Homology Domain Containing 1 (Bahd1)-dependent transcriptome in mouse E16.5 placenta and liver
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Lakisic, G, primary, Lebreton, A, additional, Pourpre, R, additional, Wendling, O, additional, Libertini, E, additional, Radford, EJ, additional, Le, Guillou, additional, Champy, MF, additional, Wattenhofer-Donzé, M, additional, Soubigou, G, additional, Ait-Si-Ali, S, additional, Feunteun, J, additional, Sorg, T, additional, Coppée, JY, additional, Ferguson-Smith, AC, additional, Cossart, P, additional, and Bierne, H, additional
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3. Analysis of the Bromo Adjacent Homology Domain Containing 1 (Bahd1)-dependent transcriptome in mouse E18.5 placenta
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Lakisic, G, primary, Lebreton, A, additional, Pourpre, R, additional, Wendling, O, additional, Libertini, E, additional, Radford, EJ, additional, Le, Guillou, additional, Champy, MF, additional, Wattenhofer-Donzé, M, additional, Soubigou, G, additional, Ait-Si-Ali, S, additional, Feunteun, J, additional, Sorg, T, additional, Coppée, JY, additional, Ferguson-Smith, AC, additional, Cossart, P, additional, and Bierne, H, additional
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4. Analysis of the Bromo Adjacent Homology Domain Containing 1 (Bahd1)-dependent transcriptome in mouse embryonic fibroblasts
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Lakisic, G, primary, Lebreton, A, additional, Pourpre, R, additional, Wendling, O, additional, Libertini, E, additional, Radford, EJ, additional, Le, Guillou, additional, Champy, MF, additional, Wattenhofer-Donzé, M, additional, Soubigou, G, additional, Ait-Si-Ali, S, additional, Feunteun, J, additional, Sorg, T, additional, Coppée, JY, additional, Ferguson-Smith, AC, additional, Cossart, P, additional, and Bierne, H, additional
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5. Loss of low-molecular-weight protein tyrosine phosphatase shows limited improvement in glucose tolerance but causes mild cardiac hypertrophy in mice.
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Jensen-Cody S, Coyne ES, Ding X, Sebin A, Vogel J, Goldstein J, Rosahl TW, Zhou HH, Jacobs H, Champy MF, About GB, Talukdar S, and Zhou Y
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- Animals, Cardiomegaly genetics, Cardiomegaly metabolism, Diet, High-Fat, Glucose metabolism, Insulin metabolism, Mice, Mice, Inbred C57BL, Mice, Obese, Protein Tyrosine Phosphatases metabolism, Protein Tyrosine Phosphatases therapeutic use, Thinness, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 genetics, Insulin Resistance genetics
- Abstract
Insulin resistance is a major public health burden that often results in other comorbidities including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease. An insulin sensitizer has the potential to become a disease-modifying therapy. It remains an unmet medical need to identify therapeutics that target the insulin signaling pathway to treat insulin resistance. Low-molecular-weight protein tyrosine phosphatase (LMPTP) negatively regulates insulin signaling and has emerged as a potential therapeutic target for insulin sensitization. Genetic studies have demonstrated that LMPTP is positively associated with obesity in humans and promotes insulin resistance in rodents. A recent study showed that pharmacological inhibition or genetic deletion of LMPTP protects mice from high-fat diet-induced insulin resistance and diabetes. Here, we show that loss of LMPTP by genetic deletion has no significant effects on improving glucose tolerance in lean or diet-induced obese mice. Furthermore, our data demonstrate that LMPTP deficiency potentiates cardiac hypertrophy that leads to mild cardiac dysfunction. Our findings suggest that the development of LMPTP inhibitors for the treatment of insulin resistance and type 2 diabetes should be reevaluated, and further studies are needed to characterize the molecular and pathophysiological role of LMPTP. NEW & NOTEWORTHY Inhibition of LMPTP with a small-molecule inhibitor, Cmpd23, improves glucose tolerance in mice as reported earlier. However, genetic deficiency of the LMPTP-encoding gene, Acp1 , has limited effects on glucose metabolism but leads to mild cardiac hypertrophy in mice. The findings suggest the potential off-target effects of Cmpd23 and call for reevaluation of LMPTP as a therapeutic target for the treatment of insulin resistance and type 2 diabetes.
- Published
- 2022
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6. Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity.
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Wang XL, Kooijman S, Gao Y, Tzeplaeff L, Cosquer B, Milanova I, Wolff SEC, Korpel N, Champy MF, Petit-Demoulière B, Goncalves Da Cruz I, Sorg-Guss T, Rensen PCN, Cassel JC, Kalsbeek A, Boutillier AL, and Yi CX
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- Animals, Circadian Rhythm physiology, Gene Knockdown Techniques, Hippocampus metabolism, Hippocampus physiology, Learning physiology, Mice, Mice, Inbred C57BL, Phagocytosis physiology, Pro-Opiomelanocortin metabolism, Stress, Physiological physiology, ARNTL Transcription Factors genetics, ARNTL Transcription Factors metabolism, Diet, High-Fat adverse effects, Memory physiology, Microglia metabolism, Obesity etiology, Obesity genetics, Obesity metabolism, Obesity prevention & control
- Abstract
Microglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In this study, we found that microglia-specific knock-down of the core clock gene, Bmal1, resulted in increased microglial phagocytosis in mice subjected to high-fat diet (HFD)-induced metabolic stress and likewise among mice engaged in critical cognitive processes. Enhanced microglial phagocytosis was associated with significant retention of pro-opiomelanocortin (POMC)-immunoreactivity in the mediobasal hypothalamus in mice on a HFD as well as the formation of mature spines in the hippocampus during the learning process. This response ultimately protected mice from HFD-induced obesity and resulted in improved performance on memory tests. We conclude that loss of the rigorous control implemented by the intrinsic clock machinery increases the extent to which microglial phagocytosis can be triggered by neighboring neurons under metabolic stress or during memory formation. Taken together, microglial responses associated with loss of Bmal1 serve to ensure a healthier microenvironment for neighboring neurons in the setting of an adaptive response. Thus, microglial Bmal1 may be an important therapeutic target for metabolic and cognitive disorders with relevance to psychiatric disease., (© 2021. The Author(s).)
- Published
- 2021
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7. SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2.
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Niewiadomska-Cimicka A, Doussau F, Perot JB, Roux MJ, Keime C, Hache A, Piguet F, Novati A, Weber C, Yalcin B, Meziane H, Champy MF, Grandgirard E, Karam A, Messaddeq N, Eisenmann A, Brouillet E, Nguyen HHP, Flament J, Isope P, and Trottier Y
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- Animals, Down-Regulation, Female, Gene Knock-In Techniques, Male, Mice, Transcriptome, Cerebellum pathology, Purkinje Cells pathology, Spinocerebellar Ataxias pathology
- Abstract
Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination because of progressive cerebellar degeneration. SCA7 is caused by polyglutamine expansion in ATXN7, a subunit of the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions in specific proteins are also responsible for SCA1-SCA3, SCA6, and SCA17; however, the converging and diverging pathomechanisms remain poorly understood. Using a new SCA7 knock-in mouse, SCA7
140Q/5Q , we analyzed gene expression in the cerebellum and assigned gene deregulation to specific cell types using published datasets. Gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks. Purkinje cells (PCs) are by far the most affected neurons and show reduced expression of 83 cell-type identity genes, including these critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphologic alterations, pacemaker dysfunction, and motor incoordination. Strikingly, most PC genes downregulated in SCA7 have also decreased expression in SCA1 and SCA2 mice, revealing converging pathomechanisms and a common disease signature involving cGMP-PKG and phosphatidylinositol signaling pathways and LTD. Our study thus points out molecular targets for therapeutic development, which may prove beneficial for several SCAs. Furthermore, we show that SCA7140Q/5Q males and females exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology, and photoreceptor dystrophy, which account for progressive impairment of behavior, motor, and visual functions. SCA7140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis. SIGNIFICANCE STATEMENT Spinocerebellar ataxia 7 (SCA7) is one of the several forms of inherited SCAs characterized by cerebellar degeneration because of polyglutamine expansion in specific proteins. The ATXN7 involved in SCA7 is a subunit of SAGA transcriptional coactivator complex. To understand the pathomechanisms of SCA7, we determined the cell type-specific gene deregulation in SCA7 mouse cerebellum. We found that the Purkinje cells are the most affected cerebellar cell type and show downregulation of a large subset of neuronal identity genes, critical for their spontaneous firing and synaptic functions. Strikingly, the same Purkinje cell genes are downregulated in mouse models of two other SCAs. Thus, our work reveals a disease signature shared among several SCAs and uncovers potential molecular targets for their treatment., (Copyright © 2021 the authors.)- Published
- 2021
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8. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.
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Swan AL, Schütt C, Rozman J, Del Mar Muñiz Moreno M, Brandmaier S, Simon M, Leuchtenberger S, Griffiths M, Brommage R, Keskivali-Bond P, Grallert H, Werner T, Teperino R, Becker L, Miller G, Moshiri A, Seavitt JR, Cissell DD, Meehan TF, Acar EF, Lelliott CJ, Flenniken AM, Champy MF, Sorg T, Ayadi A, Braun RE, Cater H, Dickinson ME, Flicek P, Gallegos J, Ghirardello EJ, Heaney JD, Jacquot S, Lally C, Logan JG, Teboul L, Mason J, Spielmann N, McKerlie C, Murray SA, Nutter LMJ, Odfalk KF, Parkinson H, Prochazka J, Reynolds CL, Selloum M, Spoutil F, Svenson KL, Vales TS, Wells SE, White JK, Sedlacek R, Wurst W, Lloyd KCK, Croucher PI, Fuchs H, Williams GR, Bassett JHD, Gailus-Durner V, Herault Y, Mallon AM, Brown SDM, Mayer-Kuckuk P, and Hrabe de Angelis M
- Subjects
- Animals, Female, Gene Ontology, Genetic Pleiotropy, Genome-Wide Association Study, Genotype, Male, Mice, Mice, Transgenic, Mutation, Osteoblasts pathology, Osteoclasts pathology, Osteoporosis metabolism, Phenotype, Promoter Regions, Genetic, Protein Interaction Maps, Sex Characteristics, Transcriptome, Bone Density genetics, Gene Expression Regulation genetics, Osteoblasts metabolism, Osteoclasts metabolism, Osteoporosis genetics
- Abstract
The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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9. Soft windowing application to improve analysis of high-throughput phenotyping data.
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Haselimashhadi H, Mason JC, Munoz-Fuentes V, López-Gómez F, Babalola K, Acar EF, Kumar V, White J, Flenniken AM, King R, Straiton E, Seavitt JR, Gaspero A, Garza A, Christianson AE, Hsu CW, Reynolds CL, Lanza DG, Lorenzo I, Green JR, Gallegos JJ, Bohat R, Samaco RC, Veeraragavan S, Kim JK, Miller G, Fuchs H, Garrett L, Becker L, Kang YK, Clary D, Cho SY, Tamura M, Tanaka N, Soo KD, Bezginov A, About GB, Champy MF, Vasseur L, Leblanc S, Meziane H, Selloum M, Reilly PT, Spielmann N, Maier H, Gailus-Durner V, Sorg T, Hiroshi M, Yuichi O, Heaney JD, Dickinson ME, Wolfgang W, Tocchini-Valentini GP, Lloyd KCK, McKerlie C, Seong JK, Yann H, de Angelis MH, Brown SDM, Smedley D, Flicek P, Mallon AM, Parkinson H, and Meehan TF
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- Animals, Genetic Association Studies, Humans, Mice, Phenotype, Population Health, Software
- Abstract
Motivation: High-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors., Results: Here we introduce 'soft windowing', a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources., Availability and Implementation: The method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press.)
- Published
- 2020
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10. High-throughput discovery of genetic determinants of circadian misalignment.
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Zhang T, Xie P, Dong Y, Liu Z, Zhou F, Pan D, Huang Z, Zhai Q, Gu Y, Wu Q, Tanaka N, Obata Y, Bradley A, Lelliott CJ, Nutter LMJ, McKerlie C, Flenniken AM, Champy MF, Sorg T, Herault Y, Angelis MH, Durner VG, Mallon AM, Brown SDM, Meehan T, Parkinson HE, Smedley D, Lloyd KCK, Yan J, Gao X, Seong JK, Wang CL, Sedlacek R, Liu Y, Rozman J, Yang L, and Xu Y
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- Amino Acid Transport System y+ genetics, Animals, Machine Learning, Male, Mice, Mice, Inbred C57BL, Mutation, Receptors, Oxytocin genetics, Repressor Proteins genetics, Serine Endopeptidases genetics, Telomere-Binding Proteins genetics, Ubiquitin-Protein Ligase Complexes genetics, Circadian Rhythm genetics
- Abstract
Circadian systems provide a fitness advantage to organisms by allowing them to adapt to daily changes of environmental cues, such as light/dark cycles. The molecular mechanism underlying the circadian clock has been well characterized. However, how internal circadian clocks are entrained with regular daily light/dark cycles remains unclear. By collecting and analyzing indirect calorimetry (IC) data from more than 2000 wild-type mice available from the International Mouse Phenotyping Consortium (IMPC), we show that the onset time and peak phase of activity and food intake rhythms are reliable parameters for screening defects of circadian misalignment. We developed a machine learning algorithm to quantify these two parameters in our misalignment screen (SyncScreener) with existing datasets and used it to screen 750 mutant mouse lines from five IMPC phenotyping centres. Mutants of five genes (Slc7a11, Rhbdl1, Spop, Ctc1 and Oxtr) were found to be associated with altered patterns of activity or food intake. By further studying the Slc7a11tm1a/tm1a mice, we confirmed its advanced activity phase phenotype in response to a simulated jetlag and skeleton photoperiod stimuli. Disruption of Slc7a11 affected the intercellular communication in the suprachiasmatic nucleus, suggesting a defect in synchronization of clock neurons. Our study has established a systematic phenotype analysis approach that can be used to uncover the mechanism of circadian entrainment in mice., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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11. Identification of genetic elements in metabolism by high-throughput mouse phenotyping.
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Rozman J, Rathkolb B, Oestereicher MA, Schütt C, Ravindranath AC, Leuchtenberger S, Sharma S, Kistler M, Willershäuser M, Brommage R, Meehan TF, Mason J, Haselimashhadi H, Hough T, Mallon AM, Wells S, Santos L, Lelliott CJ, White JK, Sorg T, Champy MF, Bower LR, Reynolds CL, Flenniken AM, Murray SA, Nutter LMJ, Svenson KL, West D, Tocchini-Valentini GP, Beaudet AL, Bosch F, Braun RB, Dobbie MS, Gao X, Herault Y, Moshiri A, Moore BA, Kent Lloyd KC, McKerlie C, Masuya H, Tanaka N, Flicek P, Parkinson HE, Sedlacek R, Seong JK, Wang CL, Moore M, Brown SD, Tschöp MH, Wurst W, Klingenspor M, Wolf E, Beckers J, Machicao F, Peter A, Staiger H, Häring HU, Grallert H, Campillos M, Maier H, Fuchs H, Gailus-Durner V, Werner T, and Hrabe de Angelis M
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- Animals, Area Under Curve, Gene Regulatory Networks, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Metabolic Diseases genetics, Mice, Mice, Knockout, Phenotype, Basal Metabolism genetics, Blood Glucose metabolism, Body Weight genetics, Diabetes Mellitus, Type 2 genetics, Obesity genetics, Oxygen Consumption genetics, Triglycerides metabolism
- Abstract
Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.
- Published
- 2018
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12. Nox4 genetic inhibition in experimental hypertension and metabolic syndrome.
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Bouabout G, Ayme-Dietrich E, Jacob H, Champy MF, Birling MC, Pavlovic G, Madeira L, Fertak LE, Petit-Demoulière B, Sorg T, Herault Y, Mudgett J, and Monassier L
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- Angiotensin II, Animals, Biomarkers blood, Blood Glucose metabolism, Cardiomegaly chemically induced, Cardiomegaly enzymology, Cardiomegaly physiopathology, Diet, High-Fat, Disease Models, Animal, Female, Fibrosis, Genetic Predisposition to Disease, Heart Rate, Hypertension chemically induced, Hypertension genetics, Hypertension physiopathology, Male, Metabolic Syndrome blood, Metabolic Syndrome genetics, Mice, Inbred C57BL, Mice, Knockout, Myocardium enzymology, Myocardium pathology, NADPH Oxidase 4 genetics, Phenotype, Reactive Oxygen Species metabolism, Time Factors, Triglycerides blood, Ventricular Remodeling, Blood Pressure genetics, Hypertension enzymology, Metabolic Syndrome enzymology, NADPH Oxidase 4 deficiency
- Abstract
Background: Metabolic syndrome is a combination of symptoms including obesity, dyslipidaemia, glucose intolerance and hypertension. Oxidative stress appears to be a pathophysiological factor that links these signs and encourages progression towards heart failure and diabetes. Nox4 is a hydrogen peroxide nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoform - found in various cardiovascular cells and tissues, but also in tissues such as the liver - which is involved in glucose and lipid homeostasis., Aims: To test whether inhibition of the Nox4 enzyme could improve blood pressure and metabolic parameters in mice receiving either angiotensin II or a high-fat diet., Methods: Systolic and diastolic arterial pressures, pulse rate and heart rate were obtained in 24 male mice (12 wild-type [WT] and 12 Nox4
-/- ) before and during 14 days of angiotensin II infusion. After angiotensin II infusion, cardiac histological remodeling was assessed. Weight and biochemical parameters were measured in 18 male and 18 female mice (nine WT and nine Nox4-/- per gender) after 10 weeks on a standard chow diet, then 15 weeks on a high-fat diet. Glucose tolerance and insulin sensitivity were tested at age 25 weeks., Results: Knock-out animals did not demonstrate a baseline blood pressure phenotype, but blocking Nox4 protected against angiotensin II-mediated arterial and pulse pressure increases. No protection against angiotensin II-induced cardiac fibrosis was observed. From a metabolic point of view, Nox4 inhibition reduced plasma triglycerides in male and female mice under a chow diet. However, Nox4 deletion did not affect the metabolic profile under a high-fat diet in males or females, but increased glucose intolerance in females., Conclusion: Our data identify Nox4 as a key source of radical oxygen species involved in hypertension and some metabolic problems., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)- Published
- 2018
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13. Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies.
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Wendling O, Champy MF, Jaubert S, Pavlovic G, Dubos A, Lindner L, Jacobs H, Mark M, Combe R, Da Cruz IG, Luche H, Mudgett JS, Rosahl T, Sorg T, Malissen M, Reilly PT, and Hérault Y
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- Animals, Gene Knockout Techniques, Mice, Survival Analysis, Multiple Organ Failure mortality, Multiple Organ Failure pathology, Proton-Translocating ATPases deficiency, Receptors, Cell Surface deficiency
- Abstract
ATP6AP2 codes for the (pro)renin receptor and is an essential component of vacuolar H+ ATPase. Activating (pro)renin for conversion of Angiotensinogen to Angiotensin makes ATP6AP2 attractive for drug intervention. Tissue-specific ATP6AP2 inactivation in mouse suggested a strong impact on various organs. Consistent with this, we found that embryonic ablation of Atp6ap2 resulted in both male hemizygous lethality and female haploinsufficiency. Next, we examined the phenotype of an induced inactivation in the adult animal, most akin to detect potential effect of functional interference of ATP6AP2 through drug therapy. Induced ablation of Atp6ap2, even without equal efficiency in all tissues (aorta, brain and kidney), resulted in rapid lethality marked by weight loss, changes in nutritional as well as blood parameters, leukocyte depletion, and bone marrow hypoplasia. Upon Atp6ap2 ablation, the colon demonstrated a rapid disruption of crypt morphology, aberrant proliferation, cell-death activation, as well as generation of microadenomas. Consequently, disruption of ATP6AP2 is extremely poorly tolerated in the adult, and severely affects various organ systems demonstrating that ATP6AP2 is an essential gene implicated in basic cellular mechanisms and necessary for multiple organ function. Accordingly, any potential drug targeting of this gene product must be strictly assessed for safety.
- Published
- 2017
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14. Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome.
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Sellier C, Buijsen RAM, He F, Natla S, Jung L, Tropel P, Gaucherot A, Jacobs H, Meziane H, Vincent A, Champy MF, Sorg T, Pavlovic G, Wattenhofer-Donze M, Birling MC, Oulad-Abdelghani M, Eberling P, Ruffenach F, Joint M, Anheim M, Martinez-Cerdeno V, Tassone F, Willemsen R, Hukema RK, Viville S, Martinat C, Todd PK, and Charlet-Berguerand N
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- Animals, Ataxia metabolism, Brain metabolism, Brain pathology, Fragile X Mental Retardation Protein metabolism, Fragile X Syndrome metabolism, Humans, Male, Mice, Mice, Transgenic, Nuclear Lamina pathology, Peptides metabolism, Real-Time Polymerase Chain Reaction, Tremor metabolism, Ataxia genetics, DNA-Binding Proteins metabolism, Fragile X Mental Retardation Protein genetics, Fragile X Syndrome genetics, Membrane Proteins metabolism, Nuclear Lamina metabolism, Peptides genetics, Protein Biosynthesis, RNA, Messenger metabolism, Tremor genetics, Trinucleotide Repeat Expansion genetics
- Abstract
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5' UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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15. Physiological Expression of AMPKγ2RG Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice.
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Yang X, Mudgett J, Bou-About G, Champy MF, Jacobs H, Monassier L, Pavlovic G, Sorg T, Herault Y, Petit-Demoulière B, Lu K, Feng W, Wang H, Ma LJ, Askew R, Erion MD, Kelley DE, Myers RW, Li C, and Guan HP
- Subjects
- Animals, Apoptosis, Disease Models, Animal, Gene Knock-In Techniques, Inflammation genetics, Inflammation pathology, Kidney metabolism, Kidney pathology, Male, Mice, Inbred C57BL, Renal Insufficiency pathology, Wolff-Parkinson-White Syndrome pathology, AMP-Activated Protein Kinases genetics, Mutation, Renal Insufficiency genetics, Wolff-Parkinson-White Syndrome genetics
- Abstract
Mutations of the AMP-activated kinase gamma 2 subunit (AMPKγ2), N488I (AMPKγ2
NI ) and R531G (AMPKγ2RG ), are associated with Wolff-Parkinson-White (WPW) syndrome, a cardiac disorder characterized by ventricular pre-excitation in humans. Cardiac-specific transgenic overexpression of human AMPKγ2NI or AMPKγ2RG leads to constitutive AMPK activation and the WPW phenotype in mice. However, overexpression of these mutant proteins also caused profound, non-physiological increase in cardiac glycogen, which might abnormally alter the true phenotype. To investigate whether physiological levels of AMPKγ2NI or AMPKγ2RG mutation cause WPW syndrome and metabolic changes in other organs, we generated two knock-in mouse lines on the C57BL/6N background harboring mutations of human AMPKγ2NI and AMPKγ2RG , respectively. Similar to the reported phenotypes of mice overexpressing AMPKγ2NI or AMPKγ2RG in the heart, both lines developed WPW syndrome and cardiac hypertrophy; however, these effects were independent of cardiac glycogen accumulation. Compared with AMPKγ2WT mice, AMPKγ2NI and AMPKγ2RG mice exhibited reduced body weight, fat mass, and liver steatosis when fed with a high fat diet (HFD). Surprisingly, AMPKγ2RG but not AMPKγ2NI mice fed with an HFD exhibited severe kidney injury characterized by glycogen accumulation, inflammation, apoptosis, cyst formation, and impaired renal function. These results demonstrate that expression of AMPKγ2NI and AMPKγ2RG mutations at physiological levels can induce beneficial metabolic effects but that this is accompanied by WPW syndrome. Our data also reveal an unexpected effect of AMPKγ2RG in the kidney, linking lifelong constitutive activation of AMPK to a potential risk for kidney dysfunction in the context of an HFD., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)- Published
- 2016
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16. How Does Circadian Rhythm Impact Salt Sensitivity of Blood Pressure in Mice? A Study in Two Close C57Bl/6 Substrains.
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Combe R, Mudgett J, El Fertak L, Champy MF, Ayme-Dietrich E, Petit-Demoulière B, Sorg T, Herault Y, Madwed JB, and Monassier L
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- Animals, Blood Pressure Determination methods, Diet, Sodium-Restricted, Heart Rate drug effects, Heart Rate physiology, Hypertension chemically induced, Male, Mice, Inbred C57BL genetics, Potassium blood, Potassium pharmacology, Potassium urine, Sodium blood, Sodium urine, Sodium Chloride, Dietary adverse effects, Sodium, Dietary adverse effects, Sodium, Dietary pharmacology, Telemetry, Blood Pressure drug effects, Blood Pressure physiology, Circadian Rhythm physiology, Hypertension physiopathology, Sodium Chloride, Dietary pharmacology
- Abstract
Background: Mouse transgenesis has provided the unique opportunity to investigate mechanisms underlying sodium kidney reabsorption as well as end organ damage. However, understanding mouse background and the experimental conditions effects on phenotypic readouts of engineered mouse lines such as blood pressure presents a challenge. Despite the ability to generate high sodium and chloride plasma levels during high-salt diet, observed changes in blood pressure are not consistent between wild-type background strains and studies., Methods: The present work was designed in an attempt to determine guidelines in the field of salt-induced hypertension by recording continuously blood pressure by telemetry in mice submitted to different sodium and potassium loaded diets and changing experimental conditions in both C57BL/6N and C57BL/6J mice strain (Normal salt vs. Low salt vs. High-salt/normal potassium vs. High salt/low potassium, standard vs. modified light cycle, Non-invasive tail cuff blood pressure vs. telemetry)., Results: In this study, we have shown that, despite a strong blood pressure (BP) basal difference between C57BL/6N and C57BL/6J mice, High salt/normal potassium diet increases BP and heart rate during the active phase only (dark period) in the same extent in both strains. On the other hand, while potassium level has no effect on salt-induced hypertension in C57BL/6N mice, high-salt/low potassium diet amplifies the effect of the high-salt challenge only in C57BL/6J mice. Indeed, in this condition, salt-induced hypertension can also be detected during light period even though this BP increase is lower compared to the one occurring during the dark period. Finally, from a methodological perspective, light cycle inversion has no effect on this circadian BP phenotype and tail-cuff method is less sensitive than telemetry to detect BP phenotypes due to salt challenges., Conclusions: Therefore, to carry investigations on salt-induced hypertension in mice, chronic telemetry and studies in the active phase are essential prerequisites.
- Published
- 2016
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17. Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism.
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Lakisic G, Lebreton A, Pourpre R, Wendling O, Libertini E, Radford EJ, Le Guillou M, Champy MF, Wattenhofer-Donzé M, Soubigou G, Ait-Si-Ali S, Feunteun J, Sorg T, Coppée JY, Ferguson-Smith AC, Cossart P, and Bierne H
- Subjects
- Animals, Chromatin genetics, Chromosomal Proteins, Non-Histone biosynthesis, DNA-Binding Proteins, Estrogen Receptor alpha genetics, Female, Gene Expression Regulation, Developmental, HEK293 Cells, Humans, Mice, Mice, Knockout, Nuclear Proteins biosynthesis, Placenta metabolism, Pregnancy, Transcription Factors biosynthesis, Transcriptome genetics, Chromosomal Proteins, Non-Histone genetics, Nuclear Proteins genetics, Placentation genetics, Steroids metabolism, Transcription Factors genetics
- Abstract
BAHD1 is a vertebrate protein that promotes heterochromatin formation and gene repression in association with several epigenetic regulators. However, its physiological roles remain unknown. Here, we demonstrate that ablation of the Bahd1 gene results in hypocholesterolemia, hypoglycemia and decreased body fat in mice. It also causes placental growth restriction with a drop of trophoblast glycogen cells, a reduction of fetal weight and a high neonatal mortality rate. By intersecting transcriptome data from murine Bahd1 knockout (KO) placentas at stages E16.5 and E18.5 of gestation, Bahd1-KO embryonic fibroblasts, and human cells stably expressing BAHD1, we also show that changes in BAHD1 levels alter expression of steroid/lipid metabolism genes. Biochemical analysis of the BAHD1-associated multiprotein complex identifies MIER proteins as novel partners of BAHD1 and suggests that BAHD1-MIER interaction forms a hub for histone deacetylases and methyltransferases, chromatin readers and transcription factors. We further show that overexpression of BAHD1 leads to an increase of MIER1 enrichment on the inactive X chromosome (Xi). In addition, BAHD1 and MIER1/3 repress expression of the steroid hormone receptor genes ESR1 and PGR, both playing important roles in placental development and energy metabolism. Moreover, modulation of BAHD1 expression in HEK293 cells triggers epigenetic changes at the ESR1 locus. Together, these results identify BAHD1 as a core component of a chromatin-repressive complex regulating placental morphogenesis and body fat storage and suggest that its dysfunction may contribute to several human diseases.
- Published
- 2016
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18. Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.
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Arbogast T, Ouagazzal AM, Chevalier C, Kopanitsa M, Afinowi N, Migliavacca E, Cowling BS, Birling MC, Champy MF, Reymond A, and Herault Y
- Subjects
- Adiposity, Alleles, Animals, Arylsulfotransferase genetics, Arylsulfotransferase metabolism, Behavior, Animal, Body Weight, Brain metabolism, Brain physiopathology, Chromosomes, Mammalian genetics, Craniofacial Abnormalities genetics, Diet, High-Fat, Disease Models, Animal, Gene Expression Profiling, Gene Expression Regulation, Gene Rearrangement genetics, Hippocampus physiopathology, Memory, Mice, Inbred C57BL, Motor Activity, Phenotype, Synaptic Transmission genetics, Syndrome, Weaning, Chromosome Deletion, Chromosome Duplication genetics, Cognition
- Abstract
The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice.
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- 2016
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19. Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome.
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Mukherji A, Kobiita A, Damara M, Misra N, Meziane H, Champy MF, and Chambon P
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- Animals, Circadian Clocks physiology, Diabetes Mellitus metabolism, Disease Models, Animal, Eating physiology, Gene Expression Regulation, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Hypercholesterolemia metabolism, Hypertriglyceridemia metabolism, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Phosphorylation, Photoperiod, Sterol Regulatory Element Binding Protein 1 metabolism, Suprachiasmatic Nucleus physiology, Time Factors, Work Schedule Tolerance, Circadian Rhythm, Feeding Behavior, Metabolic Syndrome metabolism, Period Circadian Proteins metabolism
- Abstract
The light-entrained master central circadian clock (CC) located in the suprachiasmatic nucleus (SCN) not only controls the diurnal alternance of the active phase (the light period of the human light-dark cycle, but the mouse dark period) and the rest phase (the human dark period, but the mouse light period), but also synchronizes the ubiquitous peripheral CCs (PCCs) with these phases to maintain homeostasis. We recently elucidated in mice the molecular signals through which metabolic alterations induced on an unusual feeding schedule, taking place during the rest phase [i.e., restricted feeding (RF)], creates a 12-h PCC shift. Importantly, a previous study showed that the SCN CC is unaltered during RF, which creates a misalignment between the RF-shifted PCCs and the SCN CC-controlled phases of activity and rest. However, the molecular basis of SCN CC insensitivity to RF and its possible pathological consequences are mostly unknown. Here we deciphered, at the molecular level, how RF creates this misalignment. We demonstrate that the PPARα and glucagon receptors, the two instrumental transducers in the RF-induced shift of PCCs, are not expressed in the SCN, thereby preventing on RF a shift of the master SCN CC and creating the misalignment. Most importantly, this RF-induced misalignment leads to a misexpression (with respect to their normal physiological phase of expression) of numerous CC-controlled homeostatic genes, which in the long term generates in RF mice a number of metabolic pathologies including diabetes, obesity, and metabolic syndrome, which have been reported in humans engaged in shift work schedules.
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- 2015
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20. Contribution of serotonin to cardiac remodeling associated with hypertensive diastolic ventricular dysfunction in rats.
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Ayme-Dietrich E, Marzak H, Lawson R, Mokni W, Wendling O, Combe R, Becker J, El Fertak L, Champy MF, Matz R, Andriantsitohaina R, Doly S, Boutourlinsky K, Maroteaux L, and Monassier L
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- Animals, Blood Pressure physiology, Echocardiography, Heart Failure metabolism, Heart Failure physiopathology, Heart Ventricles drug effects, Heart Ventricles metabolism, Heart Ventricles physiopathology, Hypertension physiopathology, Hypertrophy, Left Ventricular physiopathology, Male, Mice, Mice, Knockout, Natriuretic Peptide, Brain metabolism, Pyrimidines pharmacology, Rats, Rats, Inbred SHR, Receptor, Serotonin, 5-HT2A genetics, Receptor, Serotonin, 5-HT2A metabolism, Receptor, Serotonin, 5-HT2B genetics, Receptor, Serotonin, 5-HT2B metabolism, Ventricular Dysfunction, Left physiopathology, Blood Pressure drug effects, Hypertension metabolism, Hypertrophy, Left Ventricular metabolism, Serotonin metabolism, Serotonin Antagonists pharmacology, Ventricular Dysfunction, Left metabolism
- Abstract
Objective: Left-ventricular hypertrophy and interstitial fibrosis are the main pathophysiological factors of heart failure with preserved ejection fraction. Blockade of the serotonin 5-HT2B receptor (5-HT2BR) has been shown to reduce cardiac hypertrophy, oxidative stress, and extracellular cell matrix activation. In this study, we evaluated the effects of the 5-HT2BR blockade, on hemodynamic and cardiac remodeling, in spontaneously hypertensive rats (SHRs) that display a diastolic dysfunction with preserved ejection fraction., Method: Thirty-seven-week-old SHRs were randomized in four groups receiving either saline, the selective 5-HT2BR antagonist RS-127445 (1 mg/kg per day), a calcium channel blocker nicardipine (6 mg/kg per day), or RS-127445 + nicardipine. During the 14 weeks of treatment period, cardiac function and blood pressure were monitored by echocardiography and tail-cuff. Finally, electrocardiograms and invasive hemodynamics were obtained before blood collection. Heart was analyzed for morphology and mRNA expression. A complementary study evaluated the cardiac and vascular effects of serotonin on wild-type and mice knockout for the 5-HT2BR (Htr2B) and/or the 5-HT2AR (Htr2A)., Results: Despite the left ventricular 5-HT2BR overexpression, 5-HT2BR blockade by RS-127445 did not affect left ventricular hypertrophy and fibrosis in SHRs. This antagonist did not improve diastolic dysfunction, neither alone nor in combination with nicardipine, although it induced plasma brain natriuretic peptide decrease. Moreover, RS-127445 amplified subendocardial fibrosis and favored left ventricular dilatation. Finally, a subendocardial left ventricular fibrosis was induced by chronic serotonin in wild-type mice, which was increased in Htr2B animals, but prevented in Htr2A and Htr2A/2B mice, and could be explained by a contribution of the endothelial 5-HT2BRs to coronary vasodilatation., Conclusion: This work is the first to identify a cardioprotective function of the 5-HT2BR in an integrated model of diastolic dysfunction with preserved ejection fraction.
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- 2015
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21. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.
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de Angelis MH, Nicholson G, Selloum M, White J, Morgan H, Ramirez-Solis R, Sorg T, Wells S, Fuchs H, Fray M, Adams DJ, Adams NC, Adler T, Aguilar-Pimentel A, Ali-Hadji D, Amann G, André P, Atkins S, Auburtin A, Ayadi A, Becker J, Becker L, Bedu E, Bekeredjian R, Birling MC, Blake A, Bottomley J, Bowl M, Brault V, Busch DH, Bussell JN, Calzada-Wack J, Cater H, Champy MF, Charles P, Chevalier C, Chiani F, Codner GF, Combe R, Cox R, Dalloneau E, Dierich A, Di Fenza A, Doe B, Duchon A, Eickelberg O, Esapa CT, El Fertak L, Feigel T, Emelyanova I, Estabel J, Favor J, Flenniken A, Gambadoro A, Garrett L, Gates H, Gerdin AK, Gkoutos G, Greenaway S, Glasl L, Goetz P, Da Cruz IG, Götz A, Graw J, Guimond A, Hans W, Hicks G, Hölter SM, Höfler H, Hancock JM, Hoehndorf R, Hough T, Houghton R, Hurt A, Ivandic B, Jacobs H, Jacquot S, Jones N, Karp NA, Katus HA, Kitchen S, Klein-Rodewald T, Klingenspor M, Klopstock T, Lalanne V, Leblanc S, Lengger C, le Marchand E, Ludwig T, Lux A, McKerlie C, Maier H, Mandel JL, Marschall S, Mark M, Melvin DG, Meziane H, Micklich K, Mittelhauser C, Monassier L, Moulaert D, Muller S, Naton B, Neff F, Nolan PM, Nutter LM, Ollert M, Pavlovic G, Pellegata NS, Peter E, Petit-Demoulière B, Pickard A, Podrini C, Potter P, Pouilly L, Puk O, Richardson D, Rousseau S, Quintanilla-Fend L, Quwailid MM, Racz I, Rathkolb B, Riet F, Rossant J, Roux M, Rozman J, Ryder E, Salisbury J, Santos L, Schäble KH, Schiller E, Schrewe A, Schulz H, Steinkamp R, Simon M, Stewart M, Stöger C, Stöger T, Sun M, Sunter D, Teboul L, Tilly I, Tocchini-Valentini GP, Tost M, Treise I, Vasseur L, Velot E, Vogt-Weisenhorn D, Wagner C, Walling A, Weber B, Wendling O, Westerberg H, Willershäuser M, Wolf E, Wolter A, Wood J, Wurst W, Yildirim AÖ, Zeh R, Zimmer A, Zimprich A, Holmes C, Steel KP, Herault Y, Gailus-Durner V, Mallon AM, and Brown SD
- Subjects
- Animals, Female, Heterozygote, Homozygote, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Annotation, Mutation, Phenotype, Genetic Association Studies
- Abstract
The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.
- Published
- 2015
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22. Old spontaneously hypertensive rats gather together typical features of human chronic left-ventricular dysfunction with preserved ejection fraction.
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Marzak H, Ayme-Dietrich E, Lawson R, Mokni W, Combe R, Becker J, Fertak LE, Champy MF, and Monassier L
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- Animals, Blood Pressure, Body Weight, Collagen metabolism, Disease Models, Animal, Echocardiography, Fibrosis, Gene Expression Profiling, Gene Expression Regulation, Heart Failure physiopathology, Heart Rate, Heart Ventricles pathology, Humans, Male, Myocardial Contraction, Rats, Rats, Inbred SHR, Risk Factors, Ultrasonography, Doppler, Ventricular Function, Left, Aging, Diastole, Ventricular Dysfunction, Left physiopathology
- Abstract
Objective: Heart failure with preserved left-ventricular ejection fraction (HF-PEF) is an entity leading to pulmonary congestion because of impaired diastolic filling. This syndrome usually strikes those who have experienced a long history of hypertension or metabolic risk factors. Pathophysiological mechanisms are not fully understood, and standard therapy is not established. Relevant preclinical models are still lacking. The aim of this work was to evaluate aging spontaneously hypertensive rats (SHRs) as a model of HF-PEF., Methods: Serial echocardiographic and blood pressure (BP) measurements were performed in 28, 36, 43, 47 and 51-week-old SHRs and their normotensive controls (Wistar-Kyoto rats). In 52-53-week-old animals, final investigations included ECG, invasive left-ventricular (LV) and aortic catheterization, brain natriuretic peptide (BNP) plasma concentrations, ventricular reverse transcription-qPCR evaluations (β-myosin heavy chain, atrial natriuretic peptide, BNP, sarco/endoplasmic reticulum calcium ATPase 2a and collagens 1a, 3a and 2a) and cardiac histology., Results: SHRs develop a progressive alteration of the early diastole, some of the echocardiographic parameters being not sensitive to BP reduction by the calcium blocker, nicardipine. The systolic function evaluated by echocardiography and invasive catheterization was preserved. When the observation period was over, an increase in collagen synthesis and deposits were identified in subendocardial layers. This attested a probable myocardial ischemia that was confirmed by ECG changes of the ST segment. BNP increased in the blood and at the mRNA level in the myocardium., Conclusion: When aging, SHRs progressively develop HF-PEF showed by impaired LV relaxation and hypertrophy, BNP increase but preserved contractility and fibrosis. This model seems pertinent for further pharmacological preclinical studies in the field.
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- 2014
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23. Hyperactivation of Alk induces neonatal lethality in knock-in AlkF1178L mice.
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Lopez-Delisle L, Pierre-Eugène C, Bloch-Gallego E, Birling MC, Duband JL, Durand E, Bourgeois T, Matrot B, Sorg T, Huerre M, Meziane H, Roux MJ, Champy MF, Gallego J, Delattre O, and Janoueix-Lerosey I
- Subjects
- Anaplastic Lymphoma Kinase, Animals, Animals, Newborn, Genes, Lethal, Humans, Immunoenzyme Techniques, Male, Mice, Neuroblastoma metabolism, Neuroblastoma pathology, Phenotype, Behavior, Animal physiology, Eating, Mutation genetics, Neuroblastoma genetics, Receptor Protein-Tyrosine Kinases physiology, Respiration
- Abstract
The ALK (Anaplastic Lymphoma Kinase) gene encodes a tyrosine kinase receptor preferentially expressed in the central and peripheral nervous systems. A syndromic presentation associating congenital neuroblastoma with severe encephalopathy and an abnormal shape of the brainstem has been described in patients harbouring de novo germline F1174V and F1245V ALK mutations. Here, we investigated the phenotype of knock-in (KI) mice bearing the AlkF1178L mutation (F1174L in human). Although heterozygous KI mice did not reproduce the severe breathing and feeding difficulties observed in human patients, behavioral tests documented a reduced activity during dark phases and an increased anxiety of mutated mice. Matings of heterozygotes yielded the expected proportions of wild-type, heterozygotes and homozygotes at birth but a high neonatal lethality was noticed for homozygotes. We documented Alk expression in several motor nuclei of the brainstem involved in the control of sucking and swallowing. Evaluation of basic physiological functions 12 hours after birth revealed slightly more apneas but a dramatic reduced milk intake for homozygotes compared to control littermates. Overall, our data demonstrate that Alk activation above a critical threshold is not compatible with survival in mice, in agreement with the extremely severe phenotype of patients carrying aggressive de novo ALK germline mutations.
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- 2014
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24. A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains.
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Simon MM, Greenaway S, White JK, Fuchs H, Gailus-Durner V, Wells S, Sorg T, Wong K, Bedu E, Cartwright EJ, Dacquin R, Djebali S, Estabel J, Graw J, Ingham NJ, Jackson IJ, Lengeling A, Mandillo S, Marvel J, Meziane H, Preitner F, Puk O, Roux M, Adams DJ, Atkins S, Ayadi A, Becker L, Blake A, Brooker D, Cater H, Champy MF, Combe R, Danecek P, di Fenza A, Gates H, Gerdin AK, Golini E, Hancock JM, Hans W, Hölter SM, Hough T, Jurdic P, Keane TM, Morgan H, Müller W, Neff F, Nicholson G, Pasche B, Roberson LA, Rozman J, Sanderson M, Santos L, Selloum M, Shannon C, Southwell A, Tocchini-Valentini GP, Vancollie VE, Westerberg H, Wurst W, Zi M, Yalcin B, Ramirez-Solis R, Steel KP, Mallon AM, de Angelis MH, Herault Y, and Brown SD
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- Animals, Behavior, Animal, Disease Resistance immunology, Eye pathology, Female, Femur diagnostic imaging, Hypersensitivity immunology, INDEL Mutation genetics, Killer Cells, Natural immunology, Listeriosis immunology, Listeriosis microbiology, Male, Maze Learning, Mice, Inbred C57BL, Phenotype, Polymorphism, Single Nucleotide genetics, Spleen immunology, X-Ray Microtomography, Genome genetics
- Abstract
Background: The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms., Results: We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems., Conclusions: Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.
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- 2013
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25. Systems genetics of metabolism: the use of the BXD murine reference panel for multiscalar integration of traits.
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Andreux PA, Williams EG, Koutnikova H, Houtkooper RH, Champy MF, Henry H, Schoonjans K, Williams RW, and Auwerx J
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- Alkaline Phosphatase chemistry, Alkaline Phosphatase genetics, Animals, Crosses, Genetic, Female, Homeostasis, Humans, Hypophosphatasia genetics, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Polymorphism, Genetic, Quantitative Trait Loci, Reference Standards, Vitamin B 6 metabolism, Disease Models, Animal, Metabolic Diseases genetics, Mice genetics
- Abstract
Metabolic homeostasis is achieved by complex molecular and cellular networks that differ significantly among individuals and are difficult to model with genetically engineered lines of mice optimized to study single gene function. Here, we systematically acquired metabolic phenotypes by using the EUMODIC EMPReSS protocols across a large panel of isogenic but diverse strains of mice (BXD type) to study the genetic control of metabolism. We generated and analyzed 140 classical phenotypes and deposited these in an open-access web service for systems genetics (www.genenetwork.org). Heritability, influence of sex, and genetic modifiers of traits were examined singly and jointly by using quantitative-trait locus (QTL) and expression QTL-mapping methods. Traits and networks were linked to loci encompassing both known variants and novel candidate genes, including alkaline phosphatase (ALPL), here linked to hypophosphatasia. The assembled and curated phenotypes provide key resources and exemplars that can be used to dissect complex metabolic traits and disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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26. Absence of TI-VAMP/Vamp7 leads to increased anxiety in mice.
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Danglot L, Zylbersztejn K, Petkovic M, Gauberti M, Meziane H, Combe R, Champy MF, Birling MC, Pavlovic G, Bizot JC, Trovero F, Della Ragione F, Proux-Gillardeaux V, Sorg T, Vivien D, D'Esposito M, and Galli T
- Subjects
- Animals, Anxiety etiology, Anxiety psychology, COS Cells, Cells, Cultured, Chlorocebus aethiops, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Rabbits, Anxiety genetics, Metalloendopeptidases administration & dosage, R-SNARE Proteins deficiency, R-SNARE Proteins genetics, Tetanus Toxin administration & dosage
- Abstract
Vesicular (v)- and target (t)-SNARE proteins assemble in SNARE complex to mediate membrane fusion. Tetanus neurotoxin-insensitive vesicular-associated membrane protein (TI-VAMP/VAMP7), a vesicular SNARE expressed in several cell types including neurons, was previously shown to play a major role in exocytosis involved in neurite growth in cultured neurons. Here we generated a complete constitutive knock-out by deleting the exon 3 of Vamp7. Loss of TI-VAMP expression did not lead to any striking developmental or neurological defect. Knock-out mice displayed decreased brain weight and increased third ventricle volume. Axon growth appeared normal in cultured knock-out neurons. Behavioral characterization unraveled that TI-VAMP knock-out was associated with increased anxiety. Our results thus suggest compensatory mechanisms allowing the TI-VAMP knock-out mice to fulfill major developmental processes. The phenotypic traits unraveled here further indicate an unexpected role of TI-VAMP-mediated vesicular traffic in anxiety and suggest a role for TI-VAMP in higher brain functions.
- Published
- 2012
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27. Reduced body weight in male Tspan8-deficient mice.
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Champy MF, Le Voci L, Selloum M, Peterson LB, Cumiskey AM, and Blom D
- Subjects
- Animals, Antigens, Neoplasm genetics, Body Weight physiology, Diabetes Mellitus, Type 2 genetics, Female, Genome-Wide Association Study, Insulin Resistance genetics, Male, Membrane Glycoproteins genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity genetics, Sex Factors, Tetraspanins, Diabetes Mellitus, Type 2 metabolism, Insulin Resistance physiology, Membrane Glycoproteins deficiency, Obesity metabolism
- Abstract
Objective: The gene TSPAN8 was recently identified in a genome-wide association study as the most likely causal gene in a locus that was correlated with the risk of type 2 diabetes (T2D) in northern European individuals. To assess whether Tspan8 is the actual T2D-causal gene in this locus, we ablated its expression in mice and determined the consequences of this ablation on a multitude of metabolic traits., Results: We found that genetic ablation of Tspan8 in mice results in a reduction (-15.6%) in the body weight of males fed a normal chow diet and that this deficiency results in a resistance to body weight gain (-13.7%) upon feeding a high fat and high carbohydrate diet. The differences in body weight could only be detected in male mice and were the consequence of both a decrease in fat deposition, and a decrease in lean body mass (16.9 and 11%, respectively). In spite of the significant body weight difference, no changes in fasting insulin and glucose levels could be detected in Tspan8 knockout mice, nor could we identify changes in the clearance of glucose or sensitivity to insulin in oral glucose tolerance test and intraperitoneal insulin sensitivity test studies, respectively. In addition, male Tspan8 knockout mice showed significantly lower bone mineral density and phosphorus levels (6.2 and 16.6%, respectively). Expression of Tspan8 in mouse was highest in digestive tissues, but virtually absent from the pancreas. In contrast, expression of human TSPAN8 was substantial in digestive tissues, as well as pancreatic cells., Conclusions: Our results argue for a role for Tspan8 in body-weight regulation in males, but do not show differences in T2D-associated traits that were anticipated from previous human genome-wide association studies. Differences in Tspan8 expression levels in mouse and human tissues suggest that Tspan8 could fulfill different or additional physiological functions in these organisms.
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- 2011
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28. Identification of genes and networks driving cardiovascular and metabolic phenotypes in a mouse F2 intercross.
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Derry JM, Zhong H, Molony C, MacNeil D, Guhathakurta D, Zhang B, Mudgett J, Small K, El Fertak L, Guimond A, Selloum M, Zhao W, Champy MF, Monassier L, Vogt T, Cully D, Kasarskis A, and Schadt EE
- Subjects
- Animals, Blood Pressure, Body Composition, Cholesterol metabolism, Cohort Studies, Electrocardiography methods, Female, Male, Mice, Mice, Inbred C57BL, Models, Genetic, Phenotype, Cardiovascular Diseases genetics, Cardiovascular System, Crosses, Genetic, Quantitative Trait Loci
- Abstract
To identify the genes and pathways that underlie cardiovascular and metabolic phenotypes we performed an integrated analysis of a mouse C57BL/6JxA/J F2 (B6AF2) cross by relating genome-wide gene expression data from adipose, kidney, and liver tissues to physiological endpoints measured in the population. We have identified a large number of trait QTLs including loci driving variation in cardiac function on chromosomes 2 and 6 and a hotspot for adiposity, energy metabolism, and glucose traits on chromosome 8. Integration of adipose gene expression data identified a core set of genes that drive the chromosome 8 adiposity QTL. This chromosome 8 trans eQTL signature contains genes associated with mitochondrial function and oxidative phosphorylation and maps to a subnetwork with conserved function in humans that was previously implicated in human obesity. In addition, human eSNPs corresponding to orthologous genes from the signature show enrichment for association to type II diabetes in the DIAGRAM cohort, supporting the idea that the chromosome 8 locus perturbs a molecular network that in humans senses variations in DNA and in turn affects metabolic disease risk. We functionally validate predictions from this approach by demonstrating metabolic phenotypes in knockout mice for three genes from the trans eQTL signature, Akr1b8, Emr1, and Rgs2. In addition we show that the transcriptional signatures for knockout of two of these genes, Akr1b8 and Rgs2, map to the F2 network modules associated with the chromosome 8 trans eQTL signature and that these modules are in turn very significantly correlated with adiposity in the F2 population. Overall this study demonstrates how integrating gene expression data with QTL analysis in a network-based framework can aid in the elucidation of the molecular drivers of disease that can be translated from mice to humans.
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- 2010
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29. Altered lipoprotein metabolism in P2Y(13) knockout mice.
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Blom D, Yamin TT, Champy MF, Selloum M, Bedu E, Carballo-Jane E, Gerckens L, Luell S, Meurer R, Chin J, Mudgett J, and Puig O
- Subjects
- Animals, Female, Gene Expression Profiling, Liver metabolism, Male, Mice, Mice, Knockout, RNA, Messenger genetics, Receptors, Purinergic P2 genetics, Lipoproteins metabolism, Receptors, Purinergic P2 physiology
- Abstract
The purinergic receptor P2Y(13) has been shown to play a role in the uptake of holo-HDL particles in in vitro hepatocyte experiments. In order to determine the role of P2Y(13) in lipoprotein metabolism in vivo, we ablated the expression of this gene in mice. Here we show that P2Y(13) knockout mice have lower fecal concentrations of neutral sterols (-27%±2.1% in males) as well as small decreases in plasma HDL (-13.1%±3.2% in males; -17.5%±4.0% in females) levels. In addition, significant decreases were detected in serum levels of fatty acids and glycerol in female P2Y(13) knockout mice. Hepatic mRNA profiling analyses showed increased expression of SREBP-regulated cholesterol and fatty acid biosynthesis genes, while fatty acid β-oxidation genes were significantly decreased. Liver gene signatures also identified changes in PPARα-regulated transcript levels. With the exception of a small increase in bone area, P2Y(13) knockout mice do not show any additional major abnormalities, and display normal body weight, fat mass and lean body mass. No changes in insulin sensitivity and oral glucose tolerance could be detected. Taken together, our experiments assess a role for the purinergic receptor P2Y(13) in the regulation of lipoprotein metabolism and demonstrate that modulating its activity could be of benefit to the treatment of dyslipidemia in people., (2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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30. The Pro12Ala PPARgamma2 variant determines metabolism at the gene-environment interface.
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Heikkinen S, Argmann C, Feige JN, Koutnikova H, Champy MF, Dali-Youcef N, Schadt EE, Laakso M, and Auwerx J
- Subjects
- Adipose Tissue, White metabolism, Alleles, Animals, Body Mass Index, Gene Expression Regulation, Gene Knock-In Techniques, Genetic Predisposition to Disease, Insulin metabolism, Lipids blood, Longevity, Mice, Mutation, Protein Isoforms genetics, Protein Isoforms metabolism, Amino Acid Substitution, Diet, Glucose metabolism, PPAR gamma genetics, PPAR gamma physiology
- Abstract
The metabolic impact of the common peroxisome proliferator-activated receptor gamma isoform 2 (PPARgamma2) variant Pro12Ala in human populations has been widely debated. We demonstrate, using a Pro12Ala knockin model, that on chow diet, Ala/Ala mice are leaner, have improved insulin sensitivity and plasma lipid profiles, and have longer lifespans. Gene-environment interactions played a key role as high-fat feeding eliminated the beneficial effects of the Pro12Ala variant on adiposity, plasma lipids, and insulin sensitivity. The underlying molecular mechanisms involve changes in cofactor interaction and adiponectin signaling. Altogether, our results establish the Pro12Ala variant of Ppargamma2 as an important modulator in metabolic control that strongly depends on the metabolic context.
- Published
- 2009
- Full Text
- View/download PDF
31. Genetic background determines metabolic phenotypes in the mouse.
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Champy MF, Selloum M, Zeitler V, Caradec C, Jung B, Rousseau S, Pouilly L, Sorg T, and Auwerx J
- Subjects
- Age Factors, Animals, Blood Glucose analysis, Body Composition genetics, Body Composition physiology, Body Weight genetics, Bone Density genetics, Eating genetics, Erythrocyte Count, Female, Glucose Tolerance Test veterinary, Iron blood, Lipids blood, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Phenotype, Urea blood, Mice, Inbred Strains genetics, Mice, Inbred Strains metabolism
- Abstract
To evaluate the contribution of genetic background to phenotypic variation, we compared a large range of biochemical and metabolic parameters at different ages of four inbred mice strains, C57BL/6J, 129SvPas, C3HeB/FeJ, and Balb/cByJ. Our results demonstrate that important metabolic, hematologic, and biochemical differences exist between these different inbred strains. Most of these differences are gender independent and are maintained or accentuated throughout life. It is therefore imperative that the genetic background is carefully defined in phenotypic studies. Our results also argue that certain backgrounds are more suited to study a given physiologic phenomenon, as distinct mouse strains have a different propensity to develop particular biochemical, hematologic, and metabolic abnormalities. These genetic differences can furthermore be exploited to identify new genes/proteins that contribute to phenotypic abnormalities. The choice of the genetic background in which to generate and analyze genetically engineered mutant mice is important as it is, together with environmental factors, one of the most important contributors to the variability of phenotypic results.
- Published
- 2008
- Full Text
- View/download PDF
32. Variations in DNA elucidate molecular networks that cause disease.
- Author
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Chen Y, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ, Zhang C, Lamb J, Edwards S, Sieberts SK, Leonardson A, Castellini LW, Wang S, Champy MF, Zhang B, Emilsson V, Doss S, Ghazalpour A, Horvath S, Drake TA, Lusis AJ, and Schadt EE
- Subjects
- Adipose Tissue metabolism, Animals, Apolipoprotein A-II genetics, Chromosomes, Mammalian genetics, Female, Linkage Disequilibrium, Lipoprotein Lipase genetics, Liver metabolism, Lod Score, Macrophages metabolism, Male, Membrane Proteins genetics, Metabolic Syndrome enzymology, Metabolic Syndrome metabolism, Mice, Obesity enzymology, Obesity metabolism, Phenotype, Phosphoprotein Phosphatases deficiency, Phosphoprotein Phosphatases genetics, Phosphoprotein Phosphatases metabolism, Quantitative Trait Loci, Reproducibility of Results, Ribosomal Proteins genetics, Gene Regulatory Networks genetics, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Metabolic Syndrome genetics, Obesity genetics
- Abstract
Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.
- Published
- 2008
- Full Text
- View/download PDF
33. Quantitative ultrasonic tissue characterization as a new tool for continuous monitoring of chronic liver remodelling in mice.
- Author
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Guimond A, Teletin M, Garo E, D'Sa A, Selloum M, Champy MF, Vonesch JL, and Monassier L
- Subjects
- Animals, Bile Ducts surgery, Carbon Tetrachloride, Disease Models, Animal, Disease Progression, Female, Image Interpretation, Computer-Assisted, Ligation, Liver metabolism, Liver pathology, Liver Cirrhosis blood, Liver Cirrhosis chemically induced, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Male, Mice, Mice, Inbred C57BL, Reproducibility of Results, Time Factors, Collagen metabolism, Liver diagnostic imaging, Liver Cirrhosis diagnostic imaging, Ultrasonography methods
- Abstract
Background/aim: Recognition of the limitations of liver biopsies has led to the need for non-invasive tests to assess liver fibrosis from intensity and kinetic point of views. The aim of the present study was to evaluate non-invasive ultrasonic tissue characterization for the continuous monitoring of this process in mice., Methods: Twelve-week-old male and female C57Bl6/J mice were submitted to repetitive carbon-tetrachloride (CCl4) intraperitoneal injections during 8 weeks or analysed 28 days after common bile duct ligation (BDL). The extent and kinetic of the disease progression were followed by the measurement of ultrasound backscatter intensity. This was compared with histological and blood parameter analysis., Results: CCl4 induced a progressive increase in in vivo liver tissue backscatter intensity in both males and females. This increase was mainly correlated with interstitial fibrosis and, to a lower extent, with nuclear surface of the hepatocytes. A similar result was found after BDL., Conclusions: These data demonstrate for the first time in a systematic study that ultrasound tissue characterization can be used as a reliable tool to follow liver remodelling in mice continuously.
- Published
- 2007
- Full Text
- View/download PDF
34. Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure.
- Author
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Dali-Youcef N, Mataki C, Coste A, Messaddeq N, Giroud S, Blanc S, Koehl C, Champy MF, Chambon P, Fajas L, Metzger D, Schoonjans K, and Auwerx J
- Subjects
- Adipose Tissue, Brown ultrastructure, Adipose Tissue, White ultrastructure, Animals, Apoptosis, Body Weight, Cell Proliferation, Cells, Cultured, DNA, Mitochondrial analysis, Dietary Fats administration & dosage, Fibroblasts physiology, Gene Expression, Immunohistochemistry, Mice, Mice, Inbred C57BL, Retinoblastoma Protein genetics, Time Factors, Adipose Tissue, Brown physiology, Adipose Tissue, White physiology, Energy Metabolism, Obesity prevention & control, Retinoblastoma Protein physiology
- Abstract
The role of the tumor suppressor retinoblastoma protein (pRb) has been firmly established in the control of cell cycle, apoptosis, and differentiation. Recently, it was demonstrated that lack of pRb promotes a switch from white to brown adipocyte differentiation in vitro. We used the Cre-Lox system to specifically inactivate pRb in adult adipose tissue. Under a high-fat diet, pRb-deficient (pRb(ad-/-)) mice failed to gain weight because of increased energy expenditure. This protection against weight gain was caused by the activation of mitochondrial activity in white and brown fat as evidenced by histologic, electron microscopic, and gene expression studies. Moreover, pRb(-/-) mouse embryonic fibroblasts displayed higher proliferation and apoptosis rates than pRb(+/+) mouse embryonic fibroblasts, which could contribute to the altered white adipose tissue morphology. Taken together, our data support a direct role of pRb in adipocyte cell fate determination in vivo and suggest that pRb could serve as a potential therapeutic target to trigger mitochondrial activation in white adipose tissue and brown adipose tissue, favoring an increase in energy expenditure and subsequent weight loss.
- Published
- 2007
- Full Text
- View/download PDF
35. Evaluation of glucose homeostasis.
- Author
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Heikkinen S, Argmann CA, Champy MF, and Auwerx J
- Subjects
- Animals, Blood Glucose genetics, Glucose Clamp Technique instrumentation, Glucose Clamp Technique methods, Glucose Clamp Technique trends, Glucose Tolerance Test methods, Glucose Tolerance Test trends, Homeostasis genetics, Humans, Insulin administration & dosage, Mice, Models, Biological, Blood Glucose analysis, Blood Glucose physiology, Homeostasis physiology
- Abstract
Obesity and dyslipidemia are often found in association with insulin resistance (IR). These components combined with hypertension characterize the most common endocrine disorder in humans, the metabolic syndrome. Thus, in addition to profiling body weight evolution and lipid metabolites, glucose tolerance (a reflection of IR) and insulin sensitivity should also be considered as part of any metabolic phenotyping protocol. The ability to measure IR and glucose tolerance is important not only in the quest to fully understand the pathogenesis of the metabolic syndrome in the mouse, but also to test the effects of potential interventions. This unit presents a variety of tests used for this purpose, including direct blood glucose measurements, insulin measurement by ELISA, the homeostatic model assessment, glucose tolerance and insulin sensitivity tests, and the euglycemic clamp.
- Published
- 2007
- Full Text
- View/download PDF
36. Lipid and bile acid analysis.
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Argmann CA, Houten SM, Champy MF, and Auwerx J
- Subjects
- Animals, Blood Specimen Collection methods, Cholesterol analysis, Chromatography, Gel, Chromatography, High Pressure Liquid, Fasting blood, Humans, Lipid Metabolism, Mice, Reproducibility of Results, Sensitivity and Specificity, Species Specificity, Tandem Mass Spectrometry, Triglycerides analysis, Bile Acids and Salts blood, Lipids analysis
- Abstract
Lipids are important body constituents that are vital for cellular, tissue, and whole-body homeostasis. Lipids serve as crucial membrane components, constitute the body's main energy reservoir, and are important signaling molecules. As a consequence of these pleiotropic functions, many common diseases, including atherosclerosis, chronic inflammatory disorders, and obesity, have been associated with altered lipid homeostasis. Lipid abnormalities are hence increasingly analyzed in mouse models. This unit describes commonly used methods to analyze mouse lipid metabolism, with techniques that evaluate lipids both in blood and in tissues. Despite the similarities between men and mice in many aspects of metabolism, important differences also exist in the area of lipid homeostasis. These differences are discussed and should be taken into account when extrapolating lipid data from mouse to men.
- Published
- 2006
- Full Text
- View/download PDF
37. Dissociation of analgesic and hormonal responses to forced swim stress using opioid receptor knockout mice.
- Author
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Contet C, Gavériaux-Ruff C, Matifas A, Caradec C, Champy MF, and Kieffer BL
- Subjects
- Animals, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pain Measurement methods, Reaction Time physiology, Stress, Physiological psychology, Adrenocorticotropic Hormone metabolism, Analgesia methods, Corticosterone metabolism, Receptors, Opioid deficiency, Receptors, Opioid metabolism, Stress, Physiological metabolism, Swimming psychology
- Abstract
Exposure to stress triggers hormonal and behavioral responses. It has been shown that the endogenous opioid system plays a role in some physiological reactions to stress. The opioid system was described to mediate analgesia induced by mild stressors and to modulate the activation of the hypothalamic-pituitary-adrenal axis. Our study assessed the contribution of opioid receptors in stress-induced analgesia and adrenocorticotropic hormone (ACTH) and corticosterone release by a genetic approach. We performed a parallel analysis of mice deficient in mu, delta, or kappa opioid receptors, as well as of triple opioid receptor knockout mice, following exposure to a mild stress (3-min swim at 32 degrees C). In wild-type mice, stress elicited an increase in jumping latency on the hot plate, which was influenced by gender and genetic background. This analgesic response was reversed both by naloxone and by the triple mutation, and decreased in mu and delta opioid receptor knockout females. In wild-type females, stress also delayed front- and hindpaw behaviors in the hot plate test and increased tail-flick latency in the tail immersion test. Opioid receptor deletion however did not affect these stress responses. In addition, stress produced an increase in ACTH and corticosterone plasma levels. This endocrine response remained unchanged in all mutant strains. Therefore our data indicate that, under our stress conditions, the endogenous opioid system is recruited to produce some analgesia whereas it does not influence hypothalamic-pituitary-adrenal axis activity. This implies that brain circuits mediating analgesic and hormonal responses to stress can be dissociated.
- Published
- 2006
- Full Text
- View/download PDF
38. Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62.
- Author
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Rodriguez A, Durán A, Selloum M, Champy MF, Diez-Guerra FJ, Flores JM, Serrano M, Auwerx J, Diaz-Meco MT, and Moscat J
- Subjects
- 3T3-L1 Cells, Adipocytes cytology, Adipogenesis, Adipose Tissue cytology, Animals, Embryo, Mammalian metabolism, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Fibroblasts metabolism, HeLa Cells, Humans, Mice, Mice, Knockout, RNA, Messenger genetics, RNA, Messenger metabolism, Transcription Factor TFIIH, Transcription Factors genetics, Diabetes Mellitus, Type 2 metabolism, Insulin Resistance, Signal Transduction, Transcription Factors deficiency, Transcription Factors metabolism
- Abstract
Signaling cascades that control adipogenesis are essential in the regulation of body weight and obesity. The adaptor p62 controls pathways that modulate cell differentiation. We report here that p62(-/-) mice develop mature-onset obesity, leptin resistance, as well as impaired glucose and insulin intolerance. The metabolic rate was significantly reduced in p62(-/-) nonobese mice, which displayed increased mRNA levels of PPAR-gamma and reduced levels of UCP-1 in adipose tissue. Basal activity of ERK was enhanced in fat from nonobese mutant mice. Embryo fibroblasts from p62(-/-) mice differentiated better than the wild-type controls into adipocytes, which was abrogated by pharmacological inhibition of the ERK pathway. p62 is induced during adipocyte differentiation and inhibits ERK activation by direct interaction. We propose that p62 normally antagonizes basal ERK activity and adipocyte differentiation and that its loss leads to the hyperactivation of ERK that favors adipogenesis and obesity.
- Published
- 2006
- Full Text
- View/download PDF
39. Evaluation of energy homeostasis.
- Author
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Argmann CA, Champy MF, and Auwerx J
- Subjects
- Adiposity, Animals, Energy Intake, Mice, Biomedical Research methods, Energy Metabolism, Homeostasis
- Abstract
Body mass and composition reflect the combined effects of three processes: energy intake, energy partitioning (storage), and energy expenditure. Energy is released from food as it is combusted to carbon dioxide and water, and is expended as heat and work within a cell. The energy stores, mainly in adipose tissue, represent the net balance between intake and expenditure. The methods outlined in this unit evaluate these three processes by measuring food intake and lipid absorption, body fat composition, and energy expenditure. Evaluation of food intake and fat mass is a useful first-line phenotyping test indicating altered energy homeostasis. Evaluation of energy expenditure in this unit addresses obligatory basal energy expenditure (for performance of cellular and organ functions), as measured by indirect calorimetry. The combined results of these tests provide indications of the metabolic defects in a mouse model and help to identify molecular targets that cause these abnormalities.
- Published
- 2006
- Full Text
- View/download PDF
40. Mouse functional genomics requires standardization of mouse handling and housing conditions.
- Author
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Champy MF, Selloum M, Piard L, Zeitler V, Caradec C, Chambon P, and Auwerx J
- Subjects
- Animals, Humans, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Genome, Handling, Psychological, Housing, Animal standards, Laboratory Animal Science standards, Serum metabolism
- Abstract
The study of mouse models is crucial for the functional annotation of the human genome. The recent improvements in mouse genetics now moved the bottleneck in mouse functional genomics from the generation of mutant mice lines to the phenotypic analysis of these mice lines. Simple, validated, and reproducible phenotyping tests are a prerequisite to improving this phenotyping bottleneck. We analyzed here the impact of simple variations in animal handling and housing procedures, such as cage density, diet, gender, length of fasting, as well as site (retro-orbital vs. tail), timing, and anesthesia used during venipuncture, on biochemical, hematological, and metabolic/endocrine parameters in adult C57BL/6J mice. Our results, which show that minor changes in procedures can profoundly affect biological variables, underscore the importance of establishing uniform and validated animal procedures to improve reproducibility of mouse phenotypic data.
- Published
- 2004
- Full Text
- View/download PDF
41. Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice.
- Author
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Koutnikova H, Cock TA, Watanabe M, Houten SM, Champy MF, Dierich A, and Auwerx J
- Subjects
- Adipose Tissue pathology, Animals, Female, Gene Targeting, Homozygote, Lipodystrophy genetics, Lipodystrophy pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Cytoplasmic and Nuclear metabolism, Transcription Factors genetics, Transcription Factors metabolism, Adipose Tissue metabolism, Lipodystrophy metabolism, Muscles metabolism, Receptors, Cytoplasmic and Nuclear deficiency, Transcription Factors deficiency
- Abstract
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor, which controls adipocyte differentiation. We targeted with homologous recombination the PPAR gamma 2-specific exon B, resulting in a white adipose tissue knockdown of PPAR gamma. Although homozygous (PPAR gamma hyp/hyp) mice are born with similar weight as the WT mice, the PPAR gamma hyp/hyp animals become growth retarded and develop severe lipodystrophy and hyperlipidemia. Almost half of these PPAR gamma hyp/hyp mice die before adulthood, whereas the surviving PPAR gamma hyp/hyp animals overcome the growth retardation, yet remain lipodystrophic. In contrast to most lipodystrophic models, the adult PPAR gamma hyp/hyp mice only have mild glucose intolerance and do not have a fatty liver. These metabolic consequences of the lipodystrophy are relatively benign because of the induction of a compensatory gene expression program in the muscle that enables efficient oxidation of excess lipids. The PPAR gamma hyp/hyp mice unequivocally demonstrate that PPAR gamma is the master regulator of adipogenesis in vivo and establish that lipid and glucose homeostasis can be relatively well maintained in the absence of white adipose tissue.
- Published
- 2003
- Full Text
- View/download PDF
42. SRC-1 and TIF2 control energy balance between white and brown adipose tissues.
- Author
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Picard F, Géhin M, Annicotte J, Rocchi S, Champy MF, O'Malley BW, Chambon P, and Auwerx J
- Subjects
- Adipocytes metabolism, Adipocytes ultrastructure, Adipose Tissue, Brown ultrastructure, Animals, Body Weight, Cells, Cultured, Histone Acetyltransferases, Lipid Metabolism, Lipolysis genetics, Male, Mice, Mice, Knockout, Microscopy, Electron, Molecular Sequence Data, Nuclear Receptor Coactivator 1, Nuclear Receptor Coactivator 2, Oxygen Consumption genetics, Receptors, Cytoplasmic and Nuclear metabolism, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Thermogenesis genetics, Transcription Factors genetics, Transcription Factors metabolism, Adipose Tissue, Brown metabolism, Energy Metabolism genetics, Obesity genetics, Obesity metabolism, Transcription Factors deficiency
- Abstract
We have explored the effects of two members of the p160 coregulator family on energy homeostasis. TIF2-/- mice are protected against obesity and display enhanced adaptive thermogenesis, whereas SRC-1-/- mice are prone to obesity due to reduced energy expenditure. In white adipose tissue, lack of TIF2 decreases PPARgamma activity and reduces fat accumulation, whereas in brown adipose tissue it facilitates the interaction between SRC-1 and PGC-1alpha, which induces PGC-1alpha's thermogenic activity. Interestingly, a high-fat diet increases the TIF2/SRC-1 expression ratio, which may contribute to weight gain. These results reveal that the relative level of TIF2/SRC-1 can modulate energy metabolism.
- Published
- 2002
- Full Text
- View/download PDF
43. A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity.
- Author
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Rocchi S, Picard F, Vamecq J, Gelman L, Potier N, Zeyer D, Dubuquoy L, Bac P, Champy MF, Plunket KD, Leesnitzer LM, Blanchard SG, Desreumaux P, Moras D, Renaud JP, and Auwerx J
- Subjects
- Adipocytes drug effects, Amino Acids chemistry, Amino Acids metabolism, Animals, Binding Sites, Blood Glucose metabolism, Body Weight, Cell Differentiation, Cell Line, Dose-Response Relationship, Drug, Fluorenes chemistry, Fluorenes metabolism, Gene Expression Regulation physiology, Genes, Reporter, Hypoglycemic Agents pharmacology, Insulin Resistance physiology, Leucine metabolism, Ligands, Male, Mice, Mice, Inbred Strains, Molecular Structure, Protein Binding, Protein Conformation, Receptors, Cytoplasmic and Nuclear genetics, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Rosiglitazone, Spectrometry, Mass, Electrospray Ionization, Thiazoles pharmacology, Transcription Factors genetics, Transcriptional Activation, Tyrosine chemistry, Tyrosine metabolism, Adipocytes physiology, Amino Acids pharmacology, Fluorenes pharmacology, Leucine chemistry, Receptors, Cytoplasmic and Nuclear metabolism, Thiazolidinediones, Transcription Factors metabolism
- Abstract
FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPARgamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPARgamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPARgamma, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPARgamma with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPARgamma configuration induced by F-L-Leu leads to a modified pattern of target gene activation. F-L-Leu improves insulin sensitivity in normal, diet-induced glucose-intolerant, and in diabetic db/db mice, yet it has a lower adipogenic activity. These biological effects suggest that F-L-Leu is a selective PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways.
- Published
- 2001
- Full Text
- View/download PDF
44. [A trial of stimulation with tamoxifen of progesterone nuclear receptors in patients with kidney cancer].
- Author
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Jacqmin D, Champy MF, Offner M, and Bollack C
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Kidney Neoplasms drug therapy, Male, Middle Aged, Receptors, Estrogen biosynthesis, Stimulation, Chemical, Kidney Neoplasms metabolism, Receptors, Progesterone biosynthesis, Tamoxifen pharmacology
- Abstract
Stimulation of progesterone receptors synthesis by Tamoxifen was tried in 19 patients with renal cell carcinoma. No difference was found between this series and 51 controls.
- Published
- 1988
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