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Amar J.,Toulouse University Hospital Center | Amar J.,French Institute of Health and Medical Research | Chabo C.,French Institute of Health and Medical Research | Waget A.,French Institute of Health and Medical Research | And 13 more authors.
EMBO Molecular Medicine | Year: 2011

A fat-enriched diet modifies intestinal microbiota and initiates a low-grade inflammation, insulin resistance and type-2 diabetes. Here, we demonstrate that before the onset of diabetes, after only one week of a high-fat diet (HFD), live commensal intestinal bacteria are present in large numbers in the adipose tissue and the blood where they can induce inflammation. This translocation is prevented in mice lacking the microbial pattern recognition receptors Nod1 or CD14, but overtly increased in Myd88 knockout and ob/ob mouse. This 'metabolic bacteremia' is characterized by an increased co-localization with dendritic cells from the intestinal lamina propria and by an augmented intestinal mucosal adherence of non-pathogenic Escherichia coli. The bacterial translocation process from intestine towards tissue can be reversed by six weeks of treatment with the probiotic strain Bifidobacterium animalis subsp. lactis 420, which improves the animals' overall inflammatory and metabolic status. Altogether, these data demonstrate that the early onset of HFD-induced hyperglycemia is characterized by an increased bacterial translocation from intestine towards tissues, fuelling a continuous metabolic bacteremia, which could represent new therapeutic targets. © 2011 EMBO Molecular Medicine.


News Article | December 1, 2016
Site: www.eurekalert.org

(Vienna, the 01.12.2016) It promises to be a simple and elegant strategy to heal diabetes type 1: Replacing the destroyed beta-cells in the bodies of patients with newly-produced insulin-secreting cells. For years, researchers around the globe tried various approaches with stem- or adult cells in order to induce this transformation. Their effort lead to a fundamental understanding of the molecular mechanisms involved in the development of beta cells - however, a compound capable of doing the trick was missing. Then a team coordinated by Stefan Kubicek, Group Leader at CeMM, eventually got a lead: In their latest study, published in Cell (DOI: 10.1016/j.cell.2016.11.010), they showed that artemisinins hit the bulls eye. With a specially designed, fully automated assay, they tested the effects of a representative library of approved drugs on cultured alpha cells and found the malaria drug to do the required job. "With our study, we could show that artemisinins change the epigenetic program of glucagon-producing alpha cells and induce profound alterations of their biochemical function", Stefan Kubicek explains. Alpha- and beta cells form together with at least three other highly specialized cell types the so-called islets of Langerhans in the pancreas, the body's control centers for the regulation of blood sugar. Insulin, the hormone produced by beta cells, signals to reduce blood glucose, while glucagon from alpha cells has the opposite effect. But those cells are flexible: Previous studies showed that alpha cells can replenish insulin producing cells following extreme beta cell loss. The epigenetic master regulator Arx was identified as the key molecular player in the transformation process. "Arx regulates many genes that are crucial for the functionality of an alpha cell," says Stefan Kubicek. "Preceding work of our collaborator, Patrick Collombat's team showed that a genetic knock out of Arx leads to a transformation of alpha cells into beta cells." This effect, however, was only observed in live model organisms - it was completely unknown if additional factors from the surrounding cells or even distant organs play a role. To exclude those factors, Kubicek's team together with the group of Jacob HecksherSorensen at Novo Nordisk designed special alpha and beta cell lines to analyze them isolated from their environment. They proved that loss of Arx is sufficient to confer alpha cell identity and does not depend on the body's influence. With those cell lines, the researchers at CeMM where now able to test their compound library and found artemisinins to have the same effect as an Arx loss. In close collaboration with research groups at CeMM lead by Christoph Bock and Giulio Superti-Furga as well as the group of Tibor Harkany at the Medical University of Vienna they managed to elucidate the molecular mode of action by which artemisinins reshape alpha cells: The compound binds to a protein called gephyrin, that activates GABA receptors, central switches of the cellular signaling. Subsequently, the change of countless biochemical reactions lead to the production of insulin. Another study by Patrick Collombat, published in the same issue of Cell, shows that in mouse models injections of GABA also lead to the transformation of alpha into beta cells, suggesting that both substances target the same mechanism. In addition to the cell line experiments, the effect of the malaria drug was also shown in model organisms: Stefan Kubicek´s team and their collaborators (Martin Distel, CCRI Wien; Dirk Meyer, Leopold-Franzens-Universität Innsbruck; Patrick Collombat, INSERM Nice; Physiogenex, Labege) observed an increased beta cell mass and improved blood sugar homeostasis in diabetic zebrafish, mice and rats upon artemisinin delivery. As the molecular targets for artemisinins in fish, rodents and humans are very similar, chances are high that the effect on alpha cells will also occur in humans. "Obviously, the long term effect of artemisinins needs to be tested," says Stefan Kubicek. "Especially the regenerative capacity of human alpha cells is yet unknown. Furthermore, the new beta cells must be protected from the immune system. But we are confident that the discovery of artemisinins and their mode of action can form the foundation for a completely new therapy of type 1 diabetes." The Study "Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity" is published in Cell on 1st of December 2016; DOI:10.1016/j.cell.2016.11.010. Funding: This work was partially funded by the Juvenile Diabetes Research Foundation (JDRF), the European Research Council (ERC), the Medical University of Vienna, the European Molecular Biology Organization (EMBO), the NovoNordisk Foundation, the European Commission FP7 Marie Sk?odowska-Curie Actions, the Austrian Science Fund (FWF), the Austrian Academy of Sciences (ÖAW); the INSERM AVENIR program; the INSERM, the FMR, the ANR/BMBF, LABEX SIGNALIFE, the Max-Planck-Society, Club Isatis, Mr. and Mrs. Dorato, Mr. and Mrs. Peter de Marffy-Mantuano, the Fondation Générale de Santé and the Foundation Schlumberger pour l'Education et la Recherche. Stefan Kubicek studied organic chemistry in Vienna and Zürich. He received his Ph.D. in Thomas Jenuwein's group at the Institute for Molecular Pathology (IMP) in Vienna followed by postdoctoral work with Stuart Schreiber at the Broad Institute of Harvard and MIT in the U.S. He joined CeMM in 2010. He is the Head of the Chemical Screening and Platform Austria for Chemical Biology (PLACEBO) and the Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives. The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an interdisciplinary research institute committed to advancing the understanding of human diseases through basic and biomedical research. Located at the center of the Medical University of Vienna's campus, CeMM fosters a highly collaborative and interactive research mindset. Focusing on medically relevant questions, CeMM researchers concentrate on human biology and diseases like cancer and inflammation/immune disorders. In support of scientific pursuits and medical needs, CeMM provides access to cutting-edge technologies and has established a strategic interest in personalized medicine. Since 2005, Giulio Superti-Furga is the Scientific Director of CeMM. http://www. For further information please contact Mag. Wolfgang Däuble Media Relations Manager CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 wdaeuble@cemm.oeaw.ac.at http://www.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.3-4 | Award Amount: 3.94M | Year: 2008

Obesity represents the major risk factor for the cardiometabolic syndrome, which is an epidemic disease that generates a severe global socio-economic burden for the public health systems. Enhanced production of proinflammatory adipocytokines by expanded adipose tissue is now considered as a key event in the pathogenesis of this syndrome. This process involves i) the systemic release of adipokines, preferentially by visceral abdominal fat and ii) the paracrine, adipokine-mediated crosstalk between periorganic fat and different organs including skeletal and cardiac muscle. Members of the ADAPT consortium have pioneered this novel view of adipose tissue as an active endocrine organ. However, there is very limited knowledge if adipokines and their downstream signalling pathways may represent drugable targets potentially opening new avenues to combat the devastating complications linked to obesity and the cardiometabolic syndrome. Therefore, the major goal of this project is to identify novel or existing adipocytokines as drug targets that could be used to reverse obesity-associated inflammation and adverse reactions related to excess fat, as outlined in the work programme. For this purpose the mustidisciplinary ADAPT consortium has been formed which integrates basic and clinical science, bioinformatics, in silico drug design and the specific expertise of a large pharmaceutical company. To reach the objectives, a stepwise strategy will be used including i) the identification of novel adipocytokines and the cellular sources and regulation of adipokine production, ii) the analysis of intraorgan crosstalk within adipose tissue which plays a pivotal role in adipose tissue inflammation, iii) the assessment of interorgan crosstalk with a focus on skeletal and cardiac muscle and the role of brown fat and iv) the pharmacological and clinical evaluation of adipokines as drug targets and potential biomarkers.


Briand F.,Physiogenex SAS | Thieblemont Q.,Physiogenex SAS | Andre A.,French Institute of Health and Medical Research | Ouguerram K.,French Institute of Health and Medical Research | Sulpice T.,Physiogenex SAS
Clinical and Translational Science | Year: 2011

Insulin resistance and type 2 diabetes are associated with low HDL-cholesterol (HDL-c) levels, which would impair reverse cholesterol transport (RCT). A promising therapeutic strategy is to raise HDL with cholesteryl ester transfer protein (CETP) inhibitors, but their effects on RCT remains to be demonstrated in vivo. We therefore evaluated the effects of CETP inhibitor torcetrapib in CETP-apolipoprotein (apo)B100 mice made obese and insulin resistant with a 60% high-fat diet. High-fat diet over 3 months increased body weight and homeostasis model of insulin resistance index by 30% and 846%, respectively (p < 0.01 for both vs. chow-fed mice). Total cholesterol (TC) increased by 46% and HDL-c/TC ratio decreased by 28% (both p < 0.05). Compared to vehicle, high-fat-fed mice treated with torcetrapib (30 mg/kg/day, 3 weeks) showed increased HDL-c levels and HDL-c/TC ratio by 41% and 37% (both p < 0.05). Torcetrapib increased in vitro macrophage cholesterol efflux by 22% and in vivo RCT through a 118% increase in 3H-bile acids fecal excretion after 3H-cholesterol labeled macrophage injection (p < 0.01 for both). Fecal total bile acids mass was also increased by 158% (p < 0.001). In conclusion, CETP inhibition by torcetrapib improves RCT in CETP-apoB100 mice. These results emphasize the potential of CETP inhibition to prevent cardiovascular diseases. © 2011 Wiley Periodicals, Inc.


Briand F.,Physiogenex SAS | Thieblemont Q.,Physiogenex SAS | Muzotte E.,Physiogenex SAS | Sulpice T.,Physiogenex SAS
Journal of Nutrition | Year: 2012

Reverse cholesterol transport (RCT) promotes the egress of cholesterol from peripheral tissues to the liver for biliary and fecal excretion. Although not demonstrated in vivo, RCT is thought to be impaired in patients with metabolic syndrome, in which liver steatosis prevalence is relatively high. Golden Syrian hamsters were fed a nonpurified (CON) diet and normal drinking water or a high-fat (HF) diet containing 27% fat, 0.5% cholesterol, and 0.25% deoxycholate as well as 10% fructose in drinking water for 4 wk. Compared to CON, the HF diet induced insulin resistance and dyslipidemia, with significantly higher plasma non-HDL-cholesterol concentrations and cholesteryl ester transfer protein activity. The HF diet induced severe liver steatosis, with significantly higher cholesterol and TG levels compared to CON. In vivo RCT was assessed by i.p. injecting 3H-cholesterol labeled macrophages. Compared to CON, HF hamsters had significantly greater 3H-tracer recoveries in plasma, but not HDL. After 72 h, 3H-tracer recovery in HF hamsters was 318% higher in liver and 75% lower in bile (P<0.01), indicating that the HF diet impaired hepatic cholesterol fluxes. However, macrophage-derived cholesterol fecal excretion was 45% higher in HF hamsters than in CON hamsters. This effect was not related to intestinal cholesterol absorption, which was 89% higher in HF hamsters (P < 0.05), suggesting a possible upregulation of transintestinal cholesterol excretion. Our data indicate a significant increase in macrophage-derived cholesterol fecal excretion in a hamster model of metabolic syndrome, which may not compensate for the diet-induced dyslipidemia and liver steatosis. © 2012 American Society for Nutrition.


Briand F.,Physiogenex SAS | Thieblemont Q.,Physiogenex SAS | Burcelin R.,French Institute of Health and Medical Research | Sulpice T.,Physiogenex SAS
Diabetes, Obesity and Metabolism | Year: 2012

Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glycaemic control in type 2 diabetes, but their benefits on reverse cholesterol transport (RCT) remain unknown. We evaluated the effects of DPP-4i sitagliptin 500 mg/kg/day on RCT in obese insulin-resistant CETP-apoB100 transgenic mice. Metformin 300 mg/kg/day orally was used as a reference compound. Both metformin and sitagliptin showed the expected effects on glucose parameters. Although no significant effect was observed on total cholesterol and high-density lipoprotein (HDL) cholesterol levels, sitagliptin, but not metformin, increased faecal cholesterol mass excretion by 132% (p < 0.001 vs. vehicle), suggesting a potent effect on cholesterol metabolism. Mice were then injected i.p. with 3H-cholesterol labelled macrophages to measure RCT over 48 h. Compared with vehicle, sitagliptin significantly increased macrophage-derived 3H-cholesterol faecal excretion by 39%. Administration of 14C-cholesterol labelled olive oil orally showed a significant reduction of 14C-tracer plasma appearance over time with sitagliptin, indicating that this drug promotes RCT through reduced intestinal cholesterol absorption. © 2012 Blackwell Publishing Ltd.


Briand F.,Physiogenex SAS | Prunet-Marcassus B.,Physiogenex SAS | Thieblemont Q.,Physiogenex SAS | Costard C.,Physiogenex SAS | And 3 more authors.
Atherosclerosis | Year: 2014

We investigated whether raising HDL-cholesterol levels with cholesteryl ester transfer protein (CETP) inhibition improves glucose homeostasis in dyslipidemic and insulin resistant hamsters. Compared with vehicle, torcetrapib 30mg/kg/day (TOR) administered for 10 days significantly increased by ~40% both HDL-cholesterol levels and 3H-tracer appearance in HDL after 3H-cholesterol labeled macrophages i.p. injection.TOR significantly reduced fasting plasma triglycerides, glycerol and free fatty acids levels by 65%, 31% and 23%, respectively. TOR also reduced blood glucose levels and plasma insulin by 20% and 49% respectively, which led to a 60% reduction in HOMA-IR index (all p<0.01). After 3H-2-deoxyglucose and insulin injection, TOR significantly increased glucose uptake in oxidative soleus muscle, liver and heart by 26, 33 and 70%, respectively.Raising HDL levels with the CETP inhibitor torcetrapib improves glucose homeostasis in dyslipidemic and insulin resistant hamsters. Whether similar effect would be observed with other CETP inhibitors should be investigated. © 2014 Elsevier Ireland Ltd.


Briand F.,Physiogenex SAS | Treguier M.,French Institute of Health and Medical Research | Andre A.,Physiogenex SAS | Andre A.,French Institute of Health and Medical Research | And 4 more authors.
Journal of Lipid Research | Year: 2010

Liver X receptor (LXR) activation promotes reverse cholesterol transport (RCT) in rodents but has major side effects (increased triglycerides and LDL-cholesterol levels) in species expressing cholesteryl ester transfer protein (CETP). In the face of dyslipidemia, it remains unclear whether LXR activation stimulates RCT in CETP species. We therefore used a hamster model made dyslipidemic with a 0.3% cholesterol diet and treated with vehicle or LXR agonist GW3965 (30 mg/kg bid) over 10 days. To investigate RCT, radiolabeled 3 H-cholesterol macrophages or 3 H-cholesteryl oleate-HDL were then injected to measure plasma and feces radioactivity over 72 or 48 h, respectively. The cholesterol-enriched diet increased VLDL-triglycerides and total cholesterol levels in all lipoprotein fractions and strongly increased liver lipids. Overall, GW3965 failed to improve both dyslipidemia and liver steatosis. However, after 3 H-cholesterol labeled macrophage injection, GW3965 treatment signifi cantly increased the 3 H-tracer appearance by 30% in plasma over 72 h, while fecal 3 H-cholesterol excretion increased by 156% (P < 0.001). After 3 H-cholesteryl oleate-HDL injection, GW3965 increased HDL-derived cholesterol fecal excretion by 64% (P < 0.01 vs. vehicle), while plasma fractional catabolic rate remained unchanged. Despite no benefi cial effect on dyslipidemia, LXR activation promotes macrophage-to-feces RCT in dyslipidemic hamsters. These results emphasize the use of species with a more human-like lipoprotein metabolism for drug profi ling. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.


Briand F.,Physiogenex SAS | Thieblemont Q.,Physiogenex SAS | Muzotte E.,Physiogenex SAS | Sulpice T.,Physiogenex SAS
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

Objective-This study aimed to investigate whether cholesteryl ester transfer protein inhibition promotes in vivo reverse cholesterol transport in dyslipidemic hamsters. Methods and Results-In vivo reverse cholesterol transport was measured after an intravenous injection of H-cholesteryl-oleate-labeled/ oxidized low density lipoprotein particles (H-oxLDL), which are rapidly cleared from plasma by liver-resident macrophages for further H-tracer egress in plasma, high density lipoprotein (HDL), liver, and feces. A first set of hamsters made dyslipidemic with a high-fat and high-fructose diet was treated with vehicle or torcetrapib 30 mg/kg (TOR) over 2 weeks. Compared with vehicle, TOR increased apolipoprotein E-rich HDL levels and significantly increased H-tracer appearance in HDL by 30% over 72 hours after H-oxLDL injection. However, TOR did not change H-tracer recovery in liver and feces, suggesting that uptake and excretion of cholesterol deriving from apolipoprotein E-rich HDL is not stimulated. As apoE is a potent ligand for the LDL receptor, we next evaluated the effects of TOR in combination with the LDL-lowering drug berberine, which upregulates LDL receptor expression in dyslipidemic hamsters. Compared with TOR alone, treatment with TOR+berberine 150 mg/kg resulted in lower apolipoprotein E-rich HDL levels. After H-oxLDL injection, TOR+berberine significantly increased H-tracer appearance in fecal cholesterol by 109%. Conclusion-Our data suggest that cholesteryl ester transfer protein inhibition alone does not stimulate reverse cholesterol transport in dyslipidemic hamsters and that additional effects mediated by the LDL-lowering drug berberine are required to upregulate this process. © 2012 American Heart Association, Inc.


Briand F.,Physiogenex SAS | Thieblemont Q.,Physiogenex SAS | Muzotte E.,Physiogenex SAS | Burr N.,Physiogenex SAS | And 3 more authors.
European Journal of Pharmacology | Year: 2014

Cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib differentially alter LDL- and HDL-cholesterol levels, which might be related to the potency of each drug to inhibit CETP activity. We evaluated the effects of both drugs at similar levels of CETP inhibition on macrophage-to-feces reverse cholesterol transport (RCT) in hamsters. In normolipidemic hamsters, both anacetrapib 30 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~60%. After injection of 3H-cholesteryl oleate labeled HDL, anacetrapib and dalcetrapib reduced HDL-cholesteryl esters fractional catabolic rate (FCR) by 30% and 26% (both P<0.001 vs. vehicle) respectively, but only dalcetrapib increased HDL-derived 3H-tracer fecal excretion by 30% (P<0.05 vs. vehicle). After 3H-cholesterol labeled macrophage intraperitoneal injection, anacetrapib stimulated 3H-tracer appearance in HDL, but both drugs did not promote macrophage-derived 3H-tracer fecal excretion. In dyslipidemic hamsters, both anacetrapib 1 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~65% and reduced HDL-cholesteryl ester FCR by 36% (both P<0.001 vs. vehicle), but only anacetrapib increased HDL-derived 3H-tracer fecal excretion significantly by 39%. After 3H-cholesterol labeled macrophage injection, only anacetrapib 1 mg/kg QD stimulated macrophage-derived 3H-tracer appearance in HDL. These effects remained weaker than those observed with anacetrapib 60 mg/kg QD, which induced a maximal inhibition of CETP and stimulation of macrophage-derived 3H-tracer fecal excretion. In contrast, dalcetrapib 200 mg/kg BID reduced macrophage-derived 3H-tracer fecal excretion by 23% (P<0.05 vs. vehicle). In conclusion, anacetrapib and dalcetrapib differentially alter HDL metabolism and RCT in hamsters. A stronger inhibition of CETP may be required to promote macrophage-to-feces reverse cholesterol transport in dyslipidemic hamsters. © 2014 Elsevier B.V.

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