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The pathogenesis of obesity from a genomic and systems biology perspective.

ABSTRACT: The recent obesity epidemic has imposed significant health, economical, and societal concerns. However, effective preventive and therapeutic strategies are currently lacking, primarily due to a lack of comprehensive understanding of the underlying molecular mechanisms. Recent genome-wide scans of genetic variants, transcriptome, and epigenome have uncovered >50 genetic loci that predispose individuals to obesity and revealed hundreds of genes with altered transcriptional activity and/or epigenetic variations in obesity-related tissues upon various environmental challenges such as high caloric diets, lack of physical activity, and environmental chemicals. These discoveries highlight the importance of genes involved in the control of energy homeostasis and food intake by the central nervous system, as well as genes contributing to lipid metabolism, adipogenesis, fat cell differentiation, and immune response in peripheral tissues, in obesity development. Future studies that are directed to obtain a more comprehensive, systems-level understanding of disease mechanisms and that test novel therapeutic strategies aiming at systems-level normalization of the obesity-related molecular alterations are warranted.

SUBMITTER: Levian C

PROVIDER: S-EPMC4031785 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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The pathogenesis of obesity from a genomic and systems biology perspective.

Levian Candace C Ruiz Esmeralda E Yang Xia X

The Yale journal of biology and medicine 20140606 2

The recent obesity epidemic has imposed significant health, economical, and societal concerns. However, effective preventive and therapeutic strategies are currently lacking, primarily due to a lack of comprehensive understanding of the underlying molecular mechanisms. Recent genome-wide scans of genetic variants, transcriptome, and epigenome have uncovered >50 genetic loci that predispose individuals to obesity and revealed hundreds of genes with altered transcriptional activity and/or epigenet ...[more]

PMID: 24910557

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Project description:Organotin compounds are highly persistent organic pollutants that bioaccumulate in marine biota, behaving as potent endocrine disruptors. Tributyltin (TBT) has been described as an environmental obesogen, as it contributes in mammals to lipid accumulation in a mechanism mediated by PPARÎ³ and RXR. With the aim of studying the molecular mechanisms that elicit TBT-induced pathogenesis in fish, thicklip grey mullets Chelon labrosus were exposed to low (10 ng/L) and high (500 ng/L) TBT concentrations for 1, 7 and 21 days, and gene transcription and metabolome profiles were studied. With this purpose, the multitissue transcriptome of mullet was sequenced by 454 pyrosequencing obtaining 126 Mb of sequence information. Assembly and annotation allowed spotting 8330 gene signatures on an oligonucleotide microarray that was used to identify hepatic gene transcription profiles specific to each TBT exposure set-up. Functional pathway analysis revealed that early profiles were characterized by genes related to response to organic substances and to oxidative stress and glucose metabolic processes. After 21 days of exposure, enriched GO terms in both concentrations were related to lipid homeostasis with a significant regulation of steroid metabolic and cholesterol biosynthetic processes. Also, the androgen receptor signalling pathway was regulated while PPAR signalling appeared as the most significantly regulated KEGG pathway. Neutral lipid accumulation measured by Oil-Red-O histochemistry did not show any treatment-related effect but hepatic and plasma NMR and GC-MS metabolomic analysis revealed distinctive metabolites. Aqueous profiles were characterised by lactate, glucose and alanine while GC-MS revealed a whole set of discriminating polyunsaturated fatty acids. Thus, TBT pathogenesis involves alterations of lipid metabolism through a mechanism that could involve PPARÎ³-regulated processes confirming the obesogen hypothesis for TBT in fish. Thicklip grey mullets were exposed to tributyltin (TBT). 3 treatments: control, TBT low dose (10ng/L), TBT high dose (500ng/L); 3 sampling times: 1 day, 1 week, 3 weeks. 6 mullets were dissected in each sampling point and group.

Project description:BackgroundT cell proliferation and repertoire reconstitution is a hallmark of successful hematopoietic cell transplantation (HCT). This process may be modeled as a dynamical system and in such a system, precise telomere length (TL) measurement may reflect the proliferative capacity of donor T cells. TL for different chromosomes span a few orders of magnitude, and different T cell clones will display variable TL; these differences across the population are not represented when examining average TL. This study aims to develop a method that integrates the entire spectrum of TL observed within a sample to better understand the influence on clinical outcomes following HCT.MethodsTo better reflect the entire span of TL, we used data generated using the TeLSA PCR technique that provided discrete measurments of individual telomeres for each DNA sample for 72 stem cell transplant (SCT) donor-recipient pairs. Donor and recipient TeSLA TL measurements was performed on samples taken before and 90 days post HCT, respectively. Set correspondence mathematical techniques and area under the curve (AUC) calculations were used to measured donor-recipient TL differences (delta-TL) incorporating the full distribution of measured TL from each sample.ResultsTelomere band lengths ranged from 350 basepairs (BP) to 16.7 kilobases with a logarithmically declining distribution in all samples when arrayed in a descending order. Set correspondence methods yielded TL averages which were highly correlated with AUC calculations (r >0.9, p<0.001 for all). The AUC delta-TL method predicted patient overall survival (P-log rank <0.0001). HCT recipients with intermediate degrees of telomere attrition (25th-75th percentile) post-HCT experienced the best outcomes (2 years overall survival; OS=92%), whilst donors with the least (<25th percentile; 2 years OS=33%; adjusted HR vs. intermediate shortening=9.3, p=0.001) and the greatest (>75th percentile; 2 years OS=59%; adjusted HR=6.0, p=0.01) shortening had worse outcomes. By contrast, using the traditional method based on donor-recipient difference in TeSLA mean telomere length did not demonstrate survival association in this small sample set (p log-rank=0.95).ConclusionThe findings described herein suggest that the degree of donor telomere attrition may reflect T cell proliferation and alloreactivity following transplant. Accounting for the entire span of telomere lengths, could better identify post-transplant risk groups.

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The pathogenesis of obesity from a genomic and systems biology perspective.

Publications

The pathogenesis of obesity from a genomic and systems biology perspective.

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