المؤلفون: Darren Kelly, Liz Bentley, Marianne Yon, Célia Lourenço, Jack Cantillon, Roger D. Cox, Michael Cauchi, Claire Turner

المساهمون: ERC

المصدر: Scientific Reports
Scientific Reports, Vol 9, Iss 1, Pp 1-13 (2019)

مصطلحات موضوعية: 0301 basic medicine, Blood Glucose, Male, Longitudinal study, Cushing’s, lcsh:Medicine, Type 2 diabetes, Gut flora, Butyric acid, chemistry.chemical_compound, Prognostic markers, Feces, Mice, Insulin, Longitudinal Studies, lcsh:Science, Cushing Syndrome, Mice, Knockout, Multidisciplinary, biology, Chemistry, Knockout mouse, Metabolome, Female, medicine.medical_specialty, 030106 microbiology, Article, Gas Chromatography-Mass Spectrometry, Diabetes Mellitus, Experimental, 03 medical and health sciences, Internal medicine, medicine, Metabolomics, Animals, 2 diabetes, Obesity, Monitoring, Physiologic, Volatile Organic Compounds, Ethanol, lcsh:R, VOCs, medicine.disease, biology.organism_classification, Gastrointestinal Microbiome, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Arylformamidase, Multivariate Analysis, lcsh:Q, Selected-ion flow-tube mass spectrometry

الوصف: The analysis of volatile organic compounds (VOCs) as a non-invasive method for disease monitoring, such as type 2 diabetes (T2D) has shown potential over the years although not yet set in clinical practice. Longitudinal studies to date are limited and the understanding of the underlying VOC emission over the age is poorly understood. This study investigated longitudinal changes in VOCs present in faecal headspace in two mouse models of T2D – Cushing’s syndrome and single Afmid knockout mice. Longitudinal changes in bodyweight, blood glucose levels and plasma insulin concentration were also reported. Faecal headspace analysis was carried out using selected ion flow tube mass spectrometry (SIFT-MS) and thermal desorption coupled to gas chromatography-mass spectrometry (TD-GC-MS). Multivariate data analysis of the VOC profile showed differences mainly in acetic acid and butyric acid able to discriminate the groups Afmid and Cushing’s mice. Moreover, multivariate data analysis revealed statistically significant differences in VOCs between Cushing’s mice/wild-type (WT) littermates, mainly short-chain fatty acids (SCFAs), ketones, and alcohols, and longitudinal differences mainly attributed to methanol, ethanol and acetone. Afmid mice did not present statistically significant differences in their volatile faecal metabolome when compared to their respective WT littermates. The findings suggested that mice developed a diabetic phenotype and that the altered VOC profile may imply a related change in gut microbiota, particularly in Cushing’s mice. Furthermore, this study provided major evidence of age-related changes on the volatile profile of diabetic mice.

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الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0d2708929cfd45b894172b308f8882deTest
http://europepmc.org/articles/PMC6906526Test

المؤلفون: Kiran Musunuru, Aldons J. Lusis, Juan Fernández-Tajes, Michelle Simon, Lydia Quaye, Peter Arner, Jordana T. Bell, Momoko Horikoshi, Avanthi Raghavan, Andrew P. Morris, Ana Viñuela, Xiao Wang, Nam Che, Ingrid Dahlman, Qiurong Ding, Mete Civelek, Matt J. Neville, Fredrik Karpe, Siddharth Sethi, Unnur Thorsteinsdottir, Calvin Pan, Kerrin S. Small, Gudmar Thorleifsson, Pei-Chien Tsai, Mark I. McCarthy, Markku Laakso, Marianne Yon, Alison Hugill, Anubha Mahajan, Anna L. Gloyn, Marijana Todorčević, Kari Stefansson, Roger D. Cox, Julia S. El-Sayed Moustafa, Alfonso Buil, Abhishek Nag, Craig A. Glastonbury

المصدر: Small, K S, Marijana, M, Civelek, M, El-Sayed Moustafa, J S, Wang, X, Simon, M M, Tajes, J F, Mahajan, A, Horikoshi, M, Hugill, A, Glastonbury, C A, Quaye, L, Neville, M J, Sethi, S, Yon, M, Pan, C, Che, N, Vinuela, A, Tsai, P-C, Nag, A, Buil, A, Thorleifsson, G, Raghavan, A, Ding, Q, Morris, A P, Bell, J T, Thorsteinsdottir, U, Stefansson, K, Laakso, M, Dahlman, I, Arner, P, Gloyn, A L, Musunuru, K, Lusis, A J, Cox, R D, Karpe, F & McCarthy, M I 2018, ' Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition ', Nature Genetics, vol. 50, pp. 572–580 . https://doi.org/10.1038/s41588-018-0088-xTest
Nature Genetics
Small, K S, Todorčević, M, Civelek, M, El-Sayed Moustafa, J S, Wang, X, Simon, M M, Fernandez-Tajes, J, Mahajan, A, Horikoshi, M, Hugill, A, Glastonbury, C A, Quaye, L, Neville, M J, Sethi, S, Yon, M, Pan, C, Che, N, Viñuela, A, Tsai, P-C, Nag, A, Buil, A, Thorleifsson, G, Raghavan, A, Ding, Q, Morris, A P, Bell, J T, Thorsteinsdottir, U, Stefansson, K, Laakso, M, Dahlman, I, Arner, P, Gloyn, A L, Musunuru, K, Lusis, A J, Cox, R D, Karpe, F & McCarthy, M I 2018, ' Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition ', Nature Genetics, vol. 50, no. 4, pp. 572-580 . https://doi.org/10.1038/s41588-018-0088-xTest

مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, Kruppel-Like Transcription Factors, Gene Expression, Adipose tissue, KLF14, Type 2 diabetes, Biology, Genomic Imprinting, Mice, 03 medical and health sciences, chemistry.chemical_compound, Insulin resistance, Risk Factors, Internal medicine, Adipocyte, Adipocytes, Genetics, medicine, Animals, Body Fat Distribution, Humans, Allele, Alleles, Cell Size, Mice, Knockout, Sp Transcription Factors, Body Composition/genetics, Sp Transcription Factors/genetics, Sex Characteristics, Lipogenesis, medicine.disease, Mice, Inbred C57BL, Enhancer Elements, Genetic, Phenotype, 030104 developmental biology, Endocrinology, Lipogenesis/genetics, Diabetes Mellitus, Type 2, chemistry, Kruppel-Like Transcription Factors/deficiency, Body Composition, Diabetes Mellitus, Type 2/genetics, Female, Genomic imprinting, Adipocytes/pathology, Genome-Wide Association Study

الوصف: Individual risk of type 2 diabetes (T2D) is modified by perturbations of adipose mass, distribution and function. To investigate mechanisms responsible, we explored the molecular, cellular, and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression, and modulate, in trans, expression of >400 genes. We demonstrate that, in human cellular studies, reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and, in mice, adipose-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that KLF14 T2D risk-allele carriers shift body fat from gynoid to abdominal stores, and display a marked increase in adipocyte cell size: these effects on fat distribution, and the T2D-association, are female-specific. Metabolic risk associated with variation at this imprinted locus depends on both the sex of the subject, and of the parent from whom the risk-allele derives The replicated genome-wide significant T2D association signal at chr7q32.3 maps to a 45kb recombination interval, extending from 3kb to 48kb upstream of KLF141,2 (Figure 1a-c). In previous work based on microarray-derived RNA expression data, KLF14, which encodes an imprinted transcription factor, was exposed as the likely cis-effector gene for this locus in subcutaneous adipose tissue1 and revealed to be a trans-regulator of a programme of adipose tissue expression3. The KLF family of zinc-finger binding proteins have wide-ranging regulatory roles in biological processes such as proliferation, differentiation and growth4,5. However, little is known about KLF14, a single exon gene whose transcription is limited to the maternally inherited chromosome in embryonic, extra-embryonic, and adult tissue in humans and mice6.

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الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::be2a48142a73254b78b7f405200b5b31Test
https://doi.org/10.1038/s41588-018-0088-xTest

المؤلفون: Marianne Yon, Mark R. Boyett, Joseph Yanni Gerges, John P.H. Wilding, Lucy Pickavance, Kun Jian, Reza Ashrafi, Henggui Zhang, Gershan Davis, George Hart

المصدر: Journal of obesity
Journal of Obesity, Vol 2016 (2016)
Journal of Obesity

مصطلحات موضوعية: 0301 basic medicine, Male, medicine.medical_specialty, lcsh:Internal medicine, Normal diet, Article Subject, Endocrinology, Diabetes and Metabolism, Heart Ventricles, 030204 cardiovascular system & hematology, Ryanodine receptor 2, Polymerase Chain Reaction, Ventricular action potential, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Internal medicine, Gene expression, medicine, Animals, Obesity, Rats, Wistar, lcsh:RC31-1245, Voltage-dependent calcium channel, business.industry, Arrhythmias, Cardiac, A300, Dietary Fats, Rats, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Gene Expression Regulation, Ventricle, cardiovascular system, Calcium Channels, business, Erg, Research Article

الوصف: Introduction. Obesity is increasingly common and is associated with an increased prevalence of cardiac arrhythmias. The aim of this study was to see whether in obesity there is proarrhythmic gene expression of ventricular ion channels and related molecules.Methods and Results. Rats were fed on a high-fat diet and compared to control rats on a normal diet (n=8). After 8 weeks, rats on the high-fat diet showed significantly greater weight gain and higher adiposity. Left ventricle samples were removed at 8 weeks and mRNA expression of ion channels and other molecules was measured using qPCR. Obese rats had significant upregulation ofCav1.2, HCN4,Kir2.1, RYR2, NCX1, SERCA2a, and RYR2 mRNA and downregulation of ERG mRNA. In the case of HCN4, it was confirmed that there was a significant increase in protein expression. The potential effects of the mRNA changes on the ventricular action potential and intracellular Ca2+transient were predicted using computer modelling. Modelling predicted prolongation of the ventricular action potential and an increase in the intracellular Ca2+transient, both of which would be expected to be arrhythmogenic.Conclusion. High-fat diet causing obesity results in arrhythmogenic cardiac gene expression of ion channels and related molecules.

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الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::744388b604aa37b297d2b194ab146c9cTest