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Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer’s disease (AD). The focus of this review is to highlight the possible link between ozone air pollution exposure and AD incidence. This review’s approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated.

Objective Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release. Methods Glucose tolerance tests were performed in mice after administration of selective GPR120 agonist Compound A. Insulin, glucagon, and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knock-out of gpr120. Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β, and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively. Results Acute exposure to Compound A increased glucose tolerance, circulating insulin, and glucagon levels in vivo. Endogenous and/or pharmacological GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin. Conclusions Inhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part by mitigating somatostatin release., Graphical abstract Image 1, Highlights • Gpr120 was enriched in mouse somatostatin-secreting δ cells. • GPR120 activation in mouse δ cells inhibited cAMP generation and somatostatin release. • GPR120 activation in mouse δ cells potentiated insulin and glucagon secretion.

The free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these two receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice, and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double KO animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these two receptors only minimally affects glucose homeostasis in vivo in mice.

International audience; Patients with chronic kidney disease (CKD) often exhibit increased level of oxidative stress that contribute to the deterioration of renal function and uremic complications. White adipose tissue (WAT) has been recognized as a major site of production of radical oxygen species (ROS) in the context of metabolic diseases. This study was designed to decipher whether the protein bound uremic toxin p-cresyl-sulfate (p-CS) could contribute to ROS production in WAT and promote oxidative stress. Mouse 3T3-L1 adipocytes were incubated for 2 h in culture medium containing 212 μM p-CS, a concentration chosen to mimic levels encountered in end stage renal disease patients or KCl as a control and intracellular ROS production was measured using the fluorescent probe 5-6-carboxy-2',7'-dichlorodihydrofluorescein diacetate. Oxidative insult was estimated by the measurement of malondialdehyde (MDA) content and glutathione content. The effects of probenecid (1 mM) a potent inhibitor of organic anion transporter, apocynin (1 mM) an inhibitor of NADPH oxidase or common antioxidants such as α-tocopherol (2.5 μM), ascorbate (200 μM), and N-acetylcysteine (500 μM) were further evaluated. p-CS triggered a striking increase in ROS production (+228%, p \textless 0.01), in MDA content (+214%, p \textless 0.005) and a decrease in glutathione (-47%, P \textless 0.01). Pre-treatment of cells with probenecid, apocynin or antioxidants prevented the p-CS induced ROS production and oxidative insults. These results suggest that in uremic state, the intracellular accumulation of p-CS in adipose cells could contribute, through an activation of NADPH oxidase, to the redox imbalance often reported in CKD patients.

ObjectiveMaintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty-acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release.MethodsGlucose tolerance tests were performed in mice after administration of the selective GPR120 agonist Compound A. Insulin, glucagon and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knockout of gpr120. Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively.ResultsAcute exposure to Compound A increased glucose tolerance and circulating insulin and glucagon levels in vivo. Endogenous and/or pharmacological and GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and was partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin.ConclusionsInhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part via mitigating somatostatin release.

International audience; Background. The role of uraemic toxins in insulin resistance associated with chronic kidney disease (CKD) is gaining interest. p-Cresol has been defined as the intestinally generated precursor of the prototype protein-bound uraemic toxins p-cresyl sulphate (p-CS) as the main metabolite and, at a markedly lower concentration in humans, p-cresyl glucuronide (pCG). The objective of the present study was to evaluate the metabolism of p-cresol in mice and to decipher the potential role of both conjugates of p-cresol on glucosemetabolism. Methods. p-CS and p-CG were measured by high performance liquid chromatography-fluorescence in serum from control, 5/6 nephrectomized mice and mice injected intraperitoneously with either p-cresol or p-CG. The insulin sensitivity in vivo was estimated by insulin tolerance test. The insulin pathway in the presence of p-cresol, p-CG and/or p-CS was further evaluated in vitro on C2C12 muscle cells by measuring insulin-stimulated glucose uptake and the insulin signalling pathway (protein kinase B, PKB/Akt) by western blot. Results. In contrast to in humans, where p-CS is the main metabolite of p-cresol, in CKD mice both conjugates accumulated, and after chronic p-cresol administration with equivalent concentrations but a substantial difference in protein binding (96% for p-CS and

Gpr120 is a long-chain fatty acid receptor expressed in pancreatic islets, where it inhibits the secretion of somatostatin (SST) by the δ cell. SST is a negative regulator of glucoregulatory hormone secretion. However, the precise role of Gpr120 in the regulation of insulin and glucagon secretion is still unclear, as well as the specific islet cell(s) type(s) involved. Objective: This study aimed at defining the role of pancreatic δ-cell Gpr120 signaling in the regulation of islet function and glucose homeostasis. Methods: Insulin and SST secretion was measured in isolated islets from WT, Gpr120 KO and Gpr40 KO mice in 1h static incubation in the presence of 2.8 or 16.7 mM glucose with or without synthetic (Compound A, Cpd A) or endogenous (alpha-linolenic, eicosapentaenoic or docosahexaenoic acid) Gpr120 agonists. Glucagon and SST secretion was measured after 1h static incubation in response to arginine with or without Cpd A. Cpd A was administered orally to WT male mice before an oral Glucose Tolerance Test or an Arginine Test, and blood glucose and insulin or glucagon plasma levels were measured. Results: In isolated islets from WT mice, activation of Gpr120 with either Cpd A or endogenous agonists dose-dependently inhibited glucose-stimulated SST secretion, and concomitantly increased glucose-stimulated insulin secretion. Cpd A also inhibited SST secretion and potentiated glucagon secretion in response to arginine in low glucose conditions. The effects of Cpd A were unaltered in Gpr40 KO islets but disappeared in Gpr120 KO islets. Oral administration of Cpd A improved glucose tolerance and potentiated both glucose-induced insulin secretion and arginine-induced glucagon secretion. Conclusion: The results demonstrate that Gpr120 activation in islets inhibits SST secretion, potentiates insulin and glucagon secretion, and improves glycemic control. Disclosure M.L. Croze: None. S. Granziera: None. K. Vivot: None. A. Szpigel: None. J. Ghislain: None. V. Poitout: None. Funding Société Francophone du Diabète; Montreal Diabetes Research Center; Natural Sciences and Engineering Research Council of Canada

International audience; An Asinex Gold Platinium chemical library subset of 12055 compounds was screened employing docking simulations in the active site of the human FAS KS domain. Among them, 13 compounds were further evaluated for their ability to inhibit fatty acid biosynthesis. Four compounds were found to be active in particular ASN05064661 and ASN05374526 with IC50 values of 6.6 and 10.5m, respectively. A binding mode study was further conducted with these two compounds structurally related to benzene sulfonamide and aromatic polyamide. This study showed that they fit tightly with the active site with several interactions, notably with the key residues Cys161, His293, and His331.

International audience; Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer’s disease (AD). The focus of this review is to highlight the possible link between ozone air pollution exposure and AD incidence. This review’s approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated.

International audience; A growing body of evidence suggests that exposure to traffic-related air pollution is a risk factor for type 2 diabetes. Ozone, a major photochemical pollutant in urban areas, is negatively associated with fasting glucose and insulin levels, but most aspects of this association remain to be elucidated. Using an environmentally realistic concentration (0.8 parts per million), we demonstrated that exposure of rats to ozone induced whole-body insulin resistance and oxidative stress, with associated endoplasmic reticulum (ER) stress, c-Jun N-terminal kinase (JNK) activation, and disruption of insulin signaling in skeletal muscle. Bronchoalveolar lavage fluids from ozone-treated rats reproduced this effect in C2C12 myotubes, suggesting that toxic lung mediators were responsible for the phenotype. Pretreatment with the chemical chaperone 4-phenylbutyric acid, the JNK inhibitor SP600125, or the antioxidant N-acetylcysteine alleviated insulin resistance, demonstrating that ozone sequentially triggered oxidative stress, ER stress, and JNK activation to impair insulin signaling in muscle. This study is the first to report that ozone plays a causative role in the development of insulin resistance, suggesting that it could boost the development of diabetes. We therefore provide a potential mechanism linking pollutant exposure and the increased incidence of metabolic diseases.

International audience; Protein-bound uremic toxins (i.e., indoxyl sulfate or p-cresyl sulfate), produced by intestinal bacteria, are accumulated in the plasma of chronic kidney disease (CKD) patients. These toxins interact negatively with biological functions, having potent oxidative stress-inducing effects and a pathological effect on cardiovascular disease. Recent research in CKD has shown that oxidative stress and inflammation can be compounded by impaired activation of the nuclear factor (erythroid-2-related factor)-2 (Nrf2)-Kelch-like ECH associating protein-1 (Keap1) pathway, a major cellular defense mechanism. However, to date, many questions arise regarding the role of this system in CKD. For example, protein-bound uremic toxins promote oxidative stress in CKD patients, but their putative effect on the Nrf2-Keap1 system has yet to be examined in these patients. This review will focus on the putative relationship among protein-bound uremic toxins, oxidative stress, and a possible decreased expression of Nrf2 in CKD.

International audience; Zinc-alpha2-glycoprotein (ZAG), a potent cachectic factor, is increased in patients undergoing maintenance dialysis. However, there is no data for patients before initiation of renal replacement therapy. The purpose of the present study was to assess the relationship between plasma ZAG concentration and renal function in patients with a large range of glomerular filtration rate (GFR). Plasma ZAG concentration and its relationship to GFR were investigated in 71 patients with a chronic kidney disease (CKD) stage 1 to 5, 17 chronic hemodialysis (HD), 8 peritoneal dialysis (PD) and 18 non-CKD patients. Plasma ZAG concentration was 2.3-fold higher in CKD stage 5 patients and 3-fold higher in HD and PD patients compared to non-CKD controls (P\textless0.01). The hemodialysis session further increased plasma ZAG concentration (+39%, P\textless0.01). An inverse relationship was found between ZAG levels and plasma protein (rs = -0.284; P\textless0.01), albumin (rs = -0.282, P\textless0.05), hemoglobin (rs = -0.267, P\textless0.05) and HDL-cholesterol (rs = -0.264, P\textless0.05) and a positive correlation were seen with plasma urea (rs = 0.283; P\textless0.01). In multiple regression analyses, plasma urea and HDL-cholesterol were the only variables associated with plasma ZAG (r2 = 0.406, P\textless0.001). In CKD-5 patients, plasma accumulation of ZAG was not correlated with protein energy wasting. Further prospective studies are however needed to better elucidate the potential role of ZAG in end-stage renal disease.

Chronic kidney disease (CKD) is frequently associated with protein energy wasting which has been recognized as a strong predictive factor of mortality. Zinc α2-glycoprotein (ZAG) has been proposed as a new adipokine involved in body weight control through its lipid mobilizing activity. We hypothesized that the uremic environment in CKD could alter ZAG production by white adipose tissue and contribute to CKD-associated metabolic disturbances. ZAG protein was quantified in 3T3-L1 adipocytes after incubation with plasma from healthy volunteers and CKD patients (20%, v/v). ZAG was also measured in white adipose tissue (WAT) from 5/6 nephrectomized rodents (Nx5/6) and subcutaneous adipose tissue biopsies from end-stage renal disease patients. Uremic plasma induced a significant increase in ZAG synthesis in 3T3-L1 adipocytes (+124%, p

International audience; Type 2 diabetes is a complex disease characterized by a state of insulin resistance in peripheral tissues such as skeletal muscle, adipose tissue or liver. Some inositol isomers have been reported to possess insulin-mimetic activity and to be efficient in lowering blood glucose level. The aim of the present study was to assess in mice the metabolic effects of a chronic treatment with myo-inositol, the most common stereoisomer of inositol. Mice given myo-inositol treatment (0.9 or 1.2 mg g(-1) day(-1), 15 days, orally or intraperitoneally) exhibited an improved glucose tolerance due to a greater insulin sensitivity. Mice treated with myo-inositol exhibited a decreased white adipose tissue accretion (-33%, P

International audience; The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD.

Numerous oxidants are produced as by-products of aerobic cell metabolism, and there is growing evidence that they play key roles in the pathogenesis of insulin resistance. Under conditions of oxidative stress, lipid peroxidation of ω6-polyunsaturated fatty acids leads to the production of 4-hydroxy-2-nonenal (4-HNE). Several lines of evidence suggest that 4-HNE could be involved in the pathophysiology of metabolic diseases; therefore, in this study we assessed the direct effects of 4-HNE on skeletal muscle insulin sensitivity. Gastrocnemius muscle and L6 muscle cells were treated with 4-HNE. Insulin signaling was measured by Western blotting and glucose uptake using 2-deoxy-d-[3H]glucose. Carbonyl stress, glutathione content, and oxidative stress were assessed as potential mechanisms leading to insulin resistance. Protection of cells was induced by pretreatment with 3H-1,2-dithiole-3-thione, N-acetyl-cysteine, aminoguanidine, or S-adenosyl-methionine. 4-HNE induced a time- and dose-dependent decrease in insulin signaling and insulin-induced glucose uptake in muscle. It induced a state of carbonyl stress through adduction of proteins as well as a depletion in reduced glutathione and production of radical oxygen species. A pharmacological increase in glutathione pools was achieved by 3H-1,2-dithiole-3-thione and protected the cells against all deleterious effects of 4-HNE; furthermore, N-acetylcysteine, aminoguanidine, and S-adenosylmethionine prevented 4-HNE noxious effects. 4-HNE can impair insulin action in muscle cells through oxidative stress and oxidative damage to proteins, eventually leading to insulin resistance. These deleterious effects can be prevented by pretreatment with antioxidants, scavengers, or an increase in intracellular glutathione pools. Use of such molecules could represent a novel strategy to combat insulin resistance and other oxidative stress-associated pathologies.

International audience; Lipid peroxidation is one of the most important sources of endogenous toxic metabolites. 4-Hydroxy-2-nonenal (HNE) and 4-hydroxy-2-hexenal (HHE) are produced in several oxidative stress associated diseases from peroxidation of n-6 and n-3 polyunsaturated fatty acids, respectively. Both are able to form covalent adducts with many biomolecules. Particularly, proteins adduction can induce structural and conformational changes and impair biological function, which may be involved in the toxicity of hydroxy-alkenals. The aim of this study was to compare the effect of 4-hydroxy-2-alkenals to several chemically related derivatives in order to clarify the physico-chemical requirement of their toxicity. L6 muscle cells were treated with HHE, HNE and parent derivatives (acetal derivative, trans-alkenals and alkanals). Viability and necrosis were estimated using MTT, LDH and caspase-3 tests. LogLC50 (Lethal Concentration 50) was then tested for correlation with adducts formation (estimated using dinitrophenylhydrazine) and several molecular descriptors in order to establish quantitative structure-toxicity relationship (QSTR) models. The rank of derivatives toxicity, based on LC50 was: hydroxy-alkenals>acetal derivatives approximately 2-alkenals>alkanals and a high correlation was found between logLC50 and protein carbonylation. Moreover, logLC50 was correlated to the electrophilic descriptor LUMO (lowest unoccupied molecular orbital) as well as with electronegativity-related molecular descriptors such as number of oxygen atoms, partial negative surface area (PNSA3) and partial positive surface area (PPSA3). Together, these results point out the important role of the electrophilic structure and adduct formation in hydroxy-alkenals toxicity. Our present study demonstrates that 4-hydroxy-2-alkenals dramatic effects on cell viability are due to covalent adducts formation, particularly Michael adducts. This capacity is related to the electrophilic structure and reactive CC double bond, making it highly accessible for nucleophilic addition. The present study suggests that nucleophilic scavengers might protect cells against electrophile compounds and might be of possible therapeutic value in oxidative stress associated diseases.

Introduction L’insuffisance renale chronique (IRC) se complique d’une insulino-resistance peripherique dont les mecanismes moleculaires restent largement meconnus. De nombreux travaux ont mis en evidence le role central de la lipotoxicite dans le developpement de l’insulino-resistance et du diabete de type 2. Ainsi, dans le foie et dans le muscle, l’accumulation intra-cytoplasmique de triglycerides et de certains metabolites (tels les diacylglycerols et les ceramides) interfere avec la voie de signalisation de l’insuline en activant la proteine kinase C (PKC) epsilon. La presente etude a pour objet de verifier, dans un modele animal d’IRC, l’hypothese selon laquelle l’insulino-resistance associee a l’IRC pourrait etre liee a une redistribution ectopique de lipides et un phenomene de lipotoxicite. Materiels et methodes Une IRC est produite chez la souris C57BL6 grâce a une nephrectomie subtotale des 5/6 La sensibilite a l’insuline est evaluee par des tests de tolerance a l’insuline (ITT) et au glucose (GTT). L’accumulation de lipides intra-hepatiques est mesuree et la phosphorylation de l’AMPK et l’activation de PKC epsilon (i.e. sa translocation a la membrane plasmique) sont etudiees par western blotting. Resultats Les souris IRC presentent une intolerance de glucose (p Conclusion Nos resultats suggerent l’existence, dans la maladie renale chronique d’un phenomene de lipotoxicite, susceptible de contribuer au developpement de l’insulino-resistance et au risque accru de maladies cardiovasculaires.

Introduction De recentes etudes epidemiologiques suggerent que la pollution atmospherique joue un role dans le developpement du diabete de type 2. Parallelement, le stress du reticulum endoplasmique (RE) a ete mis en avant comme un acteur important dans le developpement de l’insulino-resistance. Nous avons montre qu’une exposition a l’ozone pouvait induire chez le rat un etat d’insulino-resistance. Les objectifs de cette etude sont 1) de montrer l’implication du stress du RE dans l’insulino-resistance developpee par des rongeurs exposes a de l’ozone 2) d’etudier la reversibilite d’un tel phenomene afin de mesurer l’impact d’une exposition a l’echelle humaine. Materiels et methodes Des souris Swiss et des rats Wistar ont ete exposes a de l’ozone (0,8 ppm, 16 h). La sensibilite a l’insuline est mesuree a l’aide d’un test de tolerance a l’insuline. La voie de signalisation de l’insuline et le stress du RE ont ete etudies par western blotting. Le stress du RE et la sensibilite a l’insuline sont mesures dans le muscle 24 h, 72 h et 96 h apres exposition pour evaluer la reversibilite de ces parametres apres une exposition aigue a l’ozone. Resultats Une exposition a l’ozone entraine une insulino-resistance musculaire et un stress du reticulum endoplasmique, a l’origine de defauts dans la voie de signalisation de l’insuline. Ces effets peuvent etre prevenus en inhibant le stress du reticulum endoplasmique par un pretraitement avec un chaperon chimique (acide phenylbutyrique). La sensibilite a l’insuline redevient comparable a celle des animaux controles seulement 96 h apres exposition. Le stress du RE reste egalement effectif jusqu’a 96 h apres exposition. Conclusion Une exposition aigue a l’ozone genere chez le rongeur une insulino-resistance systemique due specifiquement au developpement d’une insulino-resistance musculaire. Les effets metaboliques de l’ozone persistent 72 h apres exposition et le stress du reticulum endoplasmique joue un role preponderant dans le developpement de l’insulino-resistance.

Introduction Un flavonoide d’origine vegetale, la cirsimaritine, a demontre in vitro une puissante activite antilipogenique sur adipocytes humains isoles avec une IC50 de l’ordre du micromolaire (0,7 μM). Afin de tester le potentiel pharmacologique de cette molecule in vivo, la cirsimaritine a ete administree chroniquement chez la souris et ses effets sur l’accretion adipeuse et la sensibilite a l’insuline ont ete evalues. Materiels et methodes Des souris mâle C57Bl6 ont recu quotidiennement pendant 15 jours une injection intraperitonale de cirsimaritine (40 mg/kg) ou de son vehicule (DMSO). La sensibilite a l’insuline est mesuree lors d’un test de tolerance a l’insuline. Les masses des differents depots de tissu adipeux blanc sont evaluees au sacrifice et la cellularite du tissu adipeux blanc est analysee. Resultats Les souris traitees a la cirsimaritine presentent une diminution significative de la glycemie a jeun (− 20 %, p Conclusion Nos resultats suggerent donc que la cirsimaritine limite l’accretion adipeuse chez la souris en exercant un puissant effet anti-lipogenique sur le tissu adipeux blanc. Un traitement chronique a la cirsimaritine ameliore la sensibilite a l’insuline, reduit l’accretion adipeuse chez la souris et pourrait donc contribuer a prevenir l’obesite.