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author:("Oresic, mates")
1.  Adaptive Changes of the Insig1/SREBP1/SCD1 Set Point Help Adipose Tissue to Cope With Increased Storage Demands of Obesity 
Diabetes  2013;62(11):3697-3708.
The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.
doi:10.2337/db12-1748
PMCID: PMC3806615  PMID: 23919961
2.  Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia 
Cardiovascular Research  2011;92(1):29-38.
Aims
Peroxisome proliferator-activated receptor-γ coactivators PGC1α and PGC1β modulate mitochondrial biogenesis and energy homeostasis. The function of these transcriptional coactivators is impaired in obesity, insulin resistance, and type 2 diabetes. We searched for transcriptomic, lipidomic, and electrophysiological alterations in PGC1β−/− hearts potentially associated with increased arrhythmic risk in metabolic diseases.
Methods and results
Microarray analysis in mouse PGC1β−/− hearts confirmed down-regulation of genes related to oxidative phosphorylation and the electron transport chain and up-regulation of hypertrophy- and hypoxia-related genes. Lipidomic analysis showed increased levels of the pro-arrhythmic and pro-inflammatory lipid, lysophosphatidylcholine. PGC1β−/− mouse electrocardiograms showed irregular heartbeats and an increased incidence of polymorphic ventricular tachycardia following isoprenaline infusion. Langendorff-perfused PGC1β−/− hearts showed action potential alternans, early after-depolarizations, and ventricular tachycardia. PGC1β−/− ventricular myocytes showed oscillatory resting potentials, action potentials with early and delayed after-depolarizations, and burst firing during sustained current injection. They showed abnormal diastolic Ca2+ transients, whose amplitude and frequency were increased by isoprenaline, and Ca2+ currents with negatively shifted inactivation characteristics, with increased window currents despite unaltered levels of CACNA1C RNA transcripts. Inwardly and outward rectifying K+ currents were all increased. Quantitiative RT-PCR demonstrated increased SCN5A, KCNA5, RYR2, and Ca2+-calmodulin dependent protein kinase II expression.
Conclusion
PGC1β−/− hearts showed a lysophospholipid-induced cardiac lipotoxicity and impaired bioenergetics accompanied by an ion channel remodelling and altered Ca2+ homeostasis, converging to produce a ventricular arrhythmic phenotype particularly during adrenergic stress. This could contribute to the increased cardiac mortality associated with both metabolic and cardiac disease attributable to lysophospholipid accumulation.
doi:10.1093/cvr/cvr155
PMCID: PMC3172981  PMID: 21632884
Mitochondria; Cardiac arrhythmia; Peroxisome proliferator-activated receptor-γ coactivator 1β; Metabolic disease; Lysophosphatidylcholine
3.  Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity 
Diabetes  2011;60(7):1861-1871.
OBJECTIVE
Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed.
RESEARCH DESIGN AND METHODS
Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity.
RESULTS
FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism.
CONCLUSIONS
Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis.
doi:10.2337/db11-0030
PMCID: PMC3121443  PMID: 21593203
4.  Farnesoid x receptor deficiency improves glucose homeostasis in mouse models of obesity 
Diabetes  2011;60(7):1861-1871.
Objective
Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose and energy metabolism which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed.
Research Design and Methods
Here, we evaluate the consequences of FXR-deficiency on body weight development, lipid metabolism and insulin resistance in murine models of genetic and diet-induced obesity.
Results
FXR-deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved due to an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated due to the repression of β-oxidation genes. In agreement, liver-specific FXR-deficiency did not protect from diet-induced obesity and insulin resistance indicating a role for non-hepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner indicating that the observed improvements by FXR-deficiency are not due to indirect effects of altered BA metabolism.
Conclusions
Overall, FXR-deficiency in obesity beneficially affects body weight development and glucose homeostasis.
doi:10.2337/db11-0030
PMCID: PMC3121443  PMID: 21593203
FXR; bile acids; obesity; glucose homeostasis; insulin resistance; energy metabolism; triglyceride metabolism; bile acid sequestrants
5.  Human Tear Fluid Lipidome: From Composition to Function 
PLoS ONE  2011;6(5):e19553.
We have explored human aqueous tear fluid lipidome with an emphasis to identify the major lipids. We also address the physiological significance of the lipidome. The tears were analysed using thin layer chromatographic, enzymatic and mass spectrometric techniques. To emphasize the physiological aspect of the lipidome, we modelled the spreading of the non-polar tear fluid lipids at air-water interface in macroscopic scale with olive oil and egg yolk phosphatidylcholine. Based on enzymatic analysis the respective concentrations of choline-containing lipids, triglycerides, and cholesteryl esters were 48±14, 10±0, and 21±18 µM. Ultra performance liquid chromatography quadrupole time of flight mass spectrometry analysis showed that phosphatidylcholine and phosphatidylethanolamine were the two most common polar lipids comprising 88±6% of all identified lipids. Triglycerides were the only non-polar lipids detected in mass spectrometric analysis i.e. no cholesteryl or wax esters were identified. The spreading experiments show that the presence of polar lipids is an absolute necessity for a proper spreading of non-polar tear fluid lipids. We provide evidence that polar lipids are the most common lipid species. Furthermore, we provide a physiological rationale for the observed lipid composition. The results open insights into the functional role of lipids in the tear fluid and also aids in providing new means to understand and treat diseases of the ocular surface.
doi:10.1371/journal.pone.0019553
PMCID: PMC3088682  PMID: 21573170
6.  Quantitative Proteomics Analysis of the Nuclear Fraction of Human CD4+ Cells in the Early Phases of IL-4-induced Th2 Differentiation* 
We used stable isotope labeling with 4-plex iTRAQ (isobaric tags for relative and absolute quantification) reagents and LC-MS/MS to investigate proteomic changes in the nucleus of activated human CD4+ cells during the early stages of Th2 cell differentiation. The effects of IL-4 stimulation upon activated naïve CD4+ cells were measured in the nuclear fractions from 6 and 24 h in three biological replicates, each using pooled cord blood samples derived from seven or more individuals. In these analyses, in the order of 800 proteins were detected with two or more peptides and quantified in three biological replicates. In addition to consistent differences observed with the nuclear localization/expression of established human Th2 and Th1 markers, there were changes that suggested the involvement of several proteins either only recently reported or otherwise not known in this context. These included SATB1 and among the novel changes detected and validated an IL-4-induced increase in the level of YB1. This unique data set from human cord blood CD4+ T cells details an extensive list of protein determinations that compares with and complements previous data determined from the Jurkat cell nucleus.
doi:10.1074/mcp.M900483-MCP200
PMCID: PMC2938108  PMID: 20467038
7.  Integrating post-genomic approaches as a strategy to advance our understanding of health and disease 
Genome Medicine  2009;1(3):35.
Following the publication of the complete human genomic sequence, the post-genomic era is driven by the need to extract useful information from genomic data. Genomics, transcriptomics, proteomics, metabolomics, epidemiological data and microbial data provide different angles to our understanding of gene-environment interactions and the determinants of disease and health. Our goal and our challenge are to integrate these very different types of data and perspectives of disease into a global model suitable for dissecting the mechanisms of disease and for predicting novel therapeutic strategies. This review aims to highlight the need for and problems with complex data integration, and proposes a framework for data integration. While there are many obstacles to overcome, biological models based upon multiple datasets will probably become the basis that drives future biomedical research.
doi:10.1186/gm35
PMCID: PMC2664946  PMID: 19341506
8.  Proteomic-Based Detection of a Protein Cluster Dysregulated during Cardiovascular Development Identifies Biomarkers of Congenital Heart Defects 
PLoS ONE  2009;4(1):e4221.
Background
Cardiovascular development is vital for embryonic survival and growth. Early gestation embryo loss or malformation has been linked to yolk sac vasculopathy and congenital heart defects (CHDs). However, the molecular pathways that underlie these structural defects in humans remain largely unknown hindering the development of molecular-based diagnostic tools and novel therapies.
Methodology/Principal Findings
Murine embryos were exposed to high glucose, a condition known to induce cardiovascular defects in both animal models and humans. We further employed a mass spectrometry-based proteomics approach to identify proteins differentially expressed in embryos with defects from those with normal cardiovascular development. The proteins detected by mass spectrometry (WNT16, ST14, Pcsk1, Jumonji, Morca2a, TRPC5, and others) were validated by Western blotting and immunoflorescent staining of the yolk sac and heart. The proteins within the proteomic dataset clustered to adhesion/migration, differentiation, transport, and insulin signaling pathways. A functional role for several proteins (WNT16, ADAM15 and NOGO-A/B) was demonstrated in an ex vivo model of heart development. Additionally, a successful application of a cluster of protein biomarkers (WNT16, ST14 and Pcsk1) as a prenatal screen for CHDs was confirmed in a study of human amniotic fluid (AF) samples from women carrying normal fetuses and those with CHDs.
Conclusions/Significance
The novel finding that WNT16, ST14 and Pcsk1 protein levels increase in fetuses with CHDs suggests that these proteins may play a role in the etiology of human CHDs. The information gained through this bed-side to bench translational approach contributes to a more complete understanding of the protein pathways dysregulated during cardiovascular development and provides novel avenues for diagnostic and therapeutic interventions, beneficial to fetuses at risk for CHDs.
doi:10.1371/journal.pone.0004221
PMCID: PMC2626248  PMID: 19156209

Results 1-8 (8)