Publications by authors named "Niyazi Acar"

68 Publications

Soluble Fiber Inulin Consumption Limits Alterations of the Gut Microbiota and Hepatic Fatty Acid Metabolism Caused by High-Fat Diet.

Nutrients 2021 Mar 23;13(3). Epub 2021 Mar 23.

Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, F-21000 Dijon, France.

Diet shapes the gut microbiota which impacts hepatic lipid metabolism. Modifications in liver fat content are associated with metabolic disorders. We investigated the extent of dietary fat and fiber-induced alterations in the composition of gut microbiota and hepatic fatty acids (FAs). Mice were fed a purified low-fat diet (LFD) or high-fat diet (HFD) containing non-soluble fiber cellulose or soluble fiber inulin. HFD induced hepatic decreases in the amounts of C14:0, C16:1n-7, C18:1n-7 and increases in the amounts of C17:0, C20:0, C16:1n-9, C22:5n-3, C20:2n-6, C20:3n-6, and C22:4n-6. When incorporated in a LFD, inulin poorly affected the profile of FAs. However, when incorporated in a HFD, it (i) specifically led to an increase in the amounts of hepatic C18:0, C22:0, total polyunsaturated FAs (PUFAs), total n-6 PUFAs, C18:3n-3, and C18:2n-6, (ii) exacerbated the HFD-induced increase in the amount of C17:0, and (iii) prevented the HFD-induced increases in C16:1n-9 and C20:3n-6. Importantly, the expression/activity of some elongases and desaturases, as well as the gut microbiota composition, were impacted by the dietary fat and fiber content. To conclude, inulin modulated gut microbiota and hepatic fatty acid composition, and further investigations will determine whether a causal relationship exists between these two parameters.
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http://dx.doi.org/10.3390/nu13031037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005099PMC
March 2021

Plasma fatty acids and primary open-angle glaucoma in the elderly: the Montrachet population-based study.

BMC Ophthalmol 2021 Mar 23;21(1):146. Epub 2021 Mar 23.

Department of Ophthalmology, University Hospital, 14 rue Paul Gaffarel, 21079, Dijon CEDEX, France.

Background: To compare plasma fatty acids (FAs) between participants with primary open-angle glaucoma (POAG) and participants without neuropathy in an elderly population and to investigate specific FAs pattern in POAG.

Methods: We conducted a population-based study in participants older than 75 years. Participants underwent a comprehensive eye examination with optic nerve photographs, visual field test and optic nerve OCT with RNFL thickness measurement. Glaucomatous status was defined according to the International Society for Epidemiologic and Geographical Ophthalmology classification. Lipids were extracted from plasma and FAs methylesters prepared and analyzed by gas chromatography-mass spectrometry.

Results: Among the 1153 participants of the Montrachet study 810 were retained for analysis and 68 had POAG. The mean age was 82.11 ± 3.67. In multivariable analysis FAs levels were not different between POAG participants and controls (P = 0.078). A FAs pattern characterized by high negative weight of gamma-linoleic acid, eicosapentaenoic acid polyunsaturated FAs (PUFAs), Cis-7 hexadecenoic acid monounsaturated FAs (MUFAs) and high positive weight of eicosadienoic acid, docosatetraenoic acid, docosapentaenoic n-6, alpha linoleic acid PUFAs, eicosenoic acid MUFAs, margaric acid and behenic acid saturated FAs was positively associated with POAG. After adjustment for major confounders, individuals in the upper tertile of FAs pattern scores compared with those in the lower tertile were more likely to present POAG (OR = 3.09 [95% CI 1.29-7.40] P = 0.013).

Conclusions: We found no significant difference regarding isolated plasma FAs between participants with POAG and participants without neuropathy in elderly but specific FAs pattern might be associated with POAG.
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http://dx.doi.org/10.1186/s12886-021-01910-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986303PMC
March 2021

Reproducing diabetic retinopathy features using newly developed human induced-pluripotent stem cell-derived retinal Müller glial cells.

Glia 2021 Mar 8. Epub 2021 Mar 8.

Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France.

Muller glial cells (MGCs) are responsible for the homeostatic and metabolic support of the retina. Despite the importance of MGCs in retinal disorders, reliable and accessible human cell sources to be used to model MGC-associated diseases are lacking. Although primary human MGCs (pMGCs) can be purified from post-mortem retinal tissues, the donor scarcity limits their use. To overcome this problem, we developed a protocol to generate and bank human induced pluripotent stem cell-derived MGCs (hiMGCs). Using a transcriptome analysis, we showed that the three genetically independent hiMGCs generated were homogeneous and showed phenotypic characteristics and transcriptomic profile of pMGCs. These cells expressed key MGC markers, including Vimentin, CLU, DKK3, SOX9, SOX2, S100A16, ITGB1, and CD44 and could be cultured up to passage 8. Under our culture conditions, hiMGCs and pMGCs expressed low transcript levels of RLPB1, AQP4, KCNJ1, KCJN10, and SLC1A3. Using a disease modeling approach, we showed that hiMGCs could be used to model the features of diabetic retinopathy (DR)-associated dyslipidemia. Indeed, palmitate, a major free fatty acid with elevated plasma levels in diabetic patients, induced the expression of inflammatory cytokines found in the ocular fluid of DR patients such as CXCL8 (IL-8) and ANGPTL4. Moreover, the analysis of palmitate-treated hiMGC secretome showed an upregulation of proangiogenic factors strongly related to DR, including ANG2, Endoglin, IL-1β, CXCL8, MMP-9, PDGF-AA, and VEGF. Thus, hiMGCs could be an alternative to pMGCs and an extremely valuable tool to help to understand and model glial cell involvement in retinal disorders, including DR.
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http://dx.doi.org/10.1002/glia.23983DOI Listing
March 2021

Investigation of the spontaneous nanoemulsification process with medium- and long-chain triglycerides.

Colloids Surf B Biointerfaces 2021 Jan 27;197:111432. Epub 2020 Oct 27.

PEPITE EA4267, Labex LipSTIC, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France. Electronic address:

Oil-in-water nanoemulsions are used in numerous biomedical applications as delivery systems. The droplet size in the nanometer range and their composition were extensively developed for carrying and enhancing the absorption of lipophilic drugs and lipids of interest. In the present study, critical parameters involved in the spontaneous nanoemulsification process such as the temperature, the oil type, the surfactant-to-oil and water-to-oil ratios were investigated. The aim was to design a solvent-free procedure for the spontaneous nanoemulsification at a low temperature of a large variety of triglycerides including vegetable oils. Nanoemulsification of medium-chain triglyceride (MCT) was not dependent on the temperature while nanodroplets of long-chain triglycerides (LCT) were only obtained by reaching the cloud point of ethoxylated surfactant Kolliphor® HS15. The molar volume of triglycerides was considered as a predictive parameter governing both, the spontaneous nanoemulsification at low temperature and the Ostwald ripening rate. The physical mixture of MCT and LCT was a promising strategy to prepare stable and fine nanoemulsions at 37 °C. They were characterized by a hydrodynamic diameter comprised between 20 and 30 nm and a narrow size distribution. These findings pave the way to new applications for the parenteral nutrition and the delivery of thermosensitive drugs and lipophilic molecules such as antioxidants.
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http://dx.doi.org/10.1016/j.colsurfb.2020.111432DOI Listing
January 2021

Bioavailability and spatial distribution of fatty acids in the rat retina after dietary omega-3 supplementation.

J Lipid Res 2020 12 30;61(12):1733-1746. Epub 2020 Oct 30.

Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA.

Spatial changes of FAs in the retina in response to different dietary n-3 formulations have never been explored, although a diet rich in EPA and DHA is recommended to protect the retina against the effects of aging. In this study, Wistar rats were fed for 8 weeks with balanced diet including either EPA-containing phospholipids (PLs), EPA-containing TGs, DHA-containing PLs, or DHA-containing TGs. Qualitative changes in FA composition of plasma, erythrocytes, and retina were evaluated by gas chromatography-flame ionization detector. Following the different dietary intakes, changes to the quantity and spatial organization of PC and PE species in retina were determined by LC coupled to MS/MS and MALDI coupled to MS imaging. The omega-3 content in the lipids of plasma and erythrocytes suggests that PLs as well as TGs are good omega-3 carriers for retina. However, a significant increase in DHA content in retina was observed, especially molecular species as di-DHA-containing PC and PE, as well as an increase in very long chain PUFAs (more than 28 carbons) following PL-EPA and TG-DHA diets only. All supplemented diets triggered spatial organization changes of DHA in the photoreceptor layer around the optic nerve. Taken together, these findings suggest that dietary omega-3 supplementation can modify the content of FAs in the rat retina.
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http://dx.doi.org/10.1194/jlr.RA120001057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707163PMC
December 2020

Eye lymphatic defects induced by bone morphogenetic protein 9 deficiency have no functional consequences on intraocular pressure.

Sci Rep 2020 09 29;10(1):16040. Epub 2020 Sep 29.

University of Grenoble Alpes, Inserm, CEA, IRIG-DS-BCI, 38000, Grenoble, France.

Aqueous humor drainage is essential for the regulation of intraocular pressure (IOP), a major risk factor for glaucoma. The Schlemm's canal and the non-conventional uveoscleral pathway are known to drain aqueous humor from the eye anterior chamber. It has recently been reported that lymphatic vessels are involved in this process, and that the Schlemm's canal responds to some lymphatic regulators. We have previously shown a critical role for bone morphogenetic protein 9 (BMP9) in lymphatic vessel maturation and valve formation, with repercussions in drainage efficiency. Here, we imaged eye lymphatic vessels and analyzed the consequences of Bmp9 (Gdf2) gene invalidation. A network of lymphatic vessel hyaluronan receptor 1 (LYVE-1)-positive lymphatic vessels was observed in the corneolimbus and the conjunctiva. In contrast, LYVE-1-positive cells present in the ciliary bodies were belonging to the macrophage lineage. Although enlarged conjunctival lymphatic trunks and a reduced valve number were observed in Bmp9-KO mice, there were no morphological differences in the Schlemm's canal compared to wild type animals. Moreover, there were no functional consequences on IOP in both basal control conditions and after laser-induced ocular hypertonia. Thus, the BMP9-activated signaling pathway does not constitute a wise target for new glaucoma therapeutic strategies.
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http://dx.doi.org/10.1038/s41598-020-71877-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524742PMC
September 2020

Cohen Syndrome-Associated Cataract Is Explained by VPS13B Functions in Lens Homeostasis and Is Modified by Additional Genetic Factors.

Invest Ophthalmol Vis Sci 2020 09;61(11):18

INSERM UMR1231, Equipe GAD, Université de Bourgogne Franche Comté, Dijon, France.

Purpose: Cohen syndrome (CS) is a rare genetic disorder caused by variants of the VPS13B gene. CS patients are affected with a severe form of retinal dystrophy, and in several cases cataracts also develop. The purpose of this study was to investigate the mechanisms and risk factors for cataract in CS, as well as to report on cataract surgeries in CS patients.

Methods: To understand how VPS13B is associated with visual impairments in CS, we generated the Vps13b∆Ex3/∆Ex3 mouse model. Mice from 1 to 3 months of age were followed by ophthalmoscopy and slit-lamp examinations. Phenotypes were investigated by histology, immunohistochemistry, and western blot. Literature analysis was performed to determine specific characteristic features of cataract in CS and to identify potential genotype-phenotype correlations.

Results: Cataracts rapidly developed in 2-month-old knockout mice and were present in almost all lenses at 3 months. Eye fundi appeared normal until cataract development. Lens immunostaining revealed that cataract formation was associated with the appearance of large vacuoles in the cortical area, epithelial-mesenchymal transition, and fibrosis. In later stages, cataracts became hypermature, leading to profound retinal remodeling due to inflammatory events. Literature analysis showed that CS-related cataracts display specific features compared to other forms of retinitis pigmentosa-related cataracts, and their onset is modified by additional genetic factors. Corroboratively, we were able to isolate a subline of the Vps13b∆Ex3/∆Ex3 model with delayed cataract onset.

Conclusions: VPS13B participates in lens homeostasis, and the CS-related cataract development dynamic is linked to additional genetic factors.
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http://dx.doi.org/10.1167/iovs.61.11.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488618PMC
September 2020

Perinatal exposure to diets with different n-6:n-3 fatty acid ratios affects olfactory tissue fatty acid composition.

Sci Rep 2020 07 1;10(1):10785. Epub 2020 Jul 1.

Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000, Dijon, France.

The olfactory mucosa (OM) and the olfactory bulb (OB) are responsible for the detection and processing of olfactory signals. Like the brain and retina, they contain high levels of n-3 and n-6 polyunsaturated fatty acids (PUFAs), which are essential for the structure and function of neuronal and non-neuronal cells. Since the influence of the maternal diet on olfactory lipid profiles of the offspring has been poorly explored, we examined the effects of feeding mice during the perinatal period with diets containing an adequate linoleic acid level but either deficient in α-linolenic acid (ALA) or supplemented in n-3 long-chain PUFAs on the lipid composition of dams and weaning offspring olfactory tissues. In both the OM and OB, the low n-3 ALA diet led to a marked reduction in n-3 PUFAs with a concomitant increase in n-6 PUFAs, whereas consumption of the high n-3 PUFA diet reduced n-6 PUFAs and increased n-3 PUFAs. Structural analysis showed that the molecular species profiles of the main phospholipid classes of olfactory tissues from weaning pups were markedly affected by the maternal diets. This study demonstrates that the PUFA status of olfactory tissues is sensitive to diet composition from the early stages of development.
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http://dx.doi.org/10.1038/s41598-020-67725-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329853PMC
July 2020

Impact of a high-fat diet on the fatty acid composition of the retina.

Exp Eye Res 2020 07 5;196:108059. Epub 2020 May 5.

Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, F-21000, Dijon, France. Electronic address:

Structure and function of the retina mainly rely on its fatty acid (FA) composition. Evidence from epidemiological studies and from animal experiments indicates that FA composition of the retina is influenced by the diet. Mice under chronic high-fat diet (HFD) develop metabolic syndrome, a risk factor for diabetes that is associated with structural and functional alterations of the retina. Here, we studied the impact of chronic exposure of mice to HFD on retinal FA composition. C57BL/6 J male mice were fed either a chow diet or a HFD for 11 weeks. As expected, HFD induced weight gain, adiposity, hyperglycemia and dyslipidemia. The retinal FA composition was determined by gas chromatography coupled to flame ionization detection. No significant change in the relative abundance of total saturated FAs (SFAs), total monounsaturated FAs (MUFAs) or total polyunsaturated FAs (PUFAs) was observed. However, retinas of HFD-fed mice displayed decreased amounts of C24:0 (p = 0.0231), C16:1n-7 (p < 0.0001), C18:1n-7 (p < 0.0001), C20:3n-9 (p = 0.0425) and C20:3n-6 (p = 0.0008), and an increased amount of C20:2n-6 (p < 0.0001). In addition, the ratio of linoleic acid (C18:2n-6) to alpha-linolenic acid (C18:3n-3) was increased in the retinas of HFD-fed mice (15.0 ± 0.8 versus 11.8 ± 0.6 in HFD and CD, respectively, p = 0.0045). No modification in the contents of arachidonic acid (C20:4n-6, AA) and docosahexaenoic acid (C22:6n-3, DHA) were observed. Analysis of dimethylacetals (DMA), which are residues of plasmalogens (Pls), revealed that the amount of Pls containing octadecanal-aldehydes (DMA C18:0) was significantly increased in HFD-fed mice (p = 0.0447). This increase was, at least in part, balanced by a decrease in Pls containing 7-octadecanal-aldehydes (DMA C18:1n-7) (p = 0.0007). In conclusion, HFD had an impact on the relative proportion of essential dietary fatty acids linoleic acid and alpha-linolenic acid that are incorporated in the retina. However, this imbalance in PUFA precursors did not alter the content of the two major retinal long-chain PUFAs, AA and DHA. HFD consumption also led to alterations in the retinal SFAs, MUFAs and Pls profiles.
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http://dx.doi.org/10.1016/j.exer.2020.108059DOI Listing
July 2020

Age-Related Changes in the Gut Microbiota Modify Brain Lipid Composition.

Front Cell Infect Microbiol 2019 14;9:444. Epub 2020 Jan 14.

Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, University of Bourgogne Franche-Comté, Eye and Nutrition Research Group, Dijon, France.

Understanding the molecular mechanisms underlying the changes observed during aging is a prerequisite to design strategies to prevent age-related diseases. Aging is associated with metabolic changes, including alteration in the brain lipid metabolism. These alterations may contribute to the development of pathophysiological conditions. Modifications in the gut microbiota composition are also observed during aging. As communication axes exist between the gut microbiota and the brain and knowing that microbiota influences the host metabolism, we speculated on whether age-associated modifications in the gut microbiota could be involved in the lipid changes observed in aging brain. For that purpose, germ-free mice were colonized by the fecal microbiota of young or old donor mice. Lipid classes and fatty acid profiles were determined in the brain (cortex), plasma and liver by thin-layer chromatography on silica gel-coated quartz rods and gas chromatography. Gut colonization by microbiota of old mice resulted in a significant increase in total monounsaturated fatty acids (MUFA) and a significant decrease in the relative amounts of cholesterol and total polyunsaturated fatty acids (PUFA) in the cortex. Among the eight most represented fatty acids in the cortex, the relative abundances of five (C18:1n-9, C22:6n-3, C20:4n-6, C18:1n-7, and C20:1n-9) were significantly altered in mice inoculated with an aged microbiota. Liquid chromatography analyses revealed that the relative abundance of major species among phosphatidyl and plasmenylcholine (PC 16:0/18:1), phosphatidyl and plasmenylethanolamine (PE 18:0/22:6), lysophosphatidylethanolamine (LPE 22:6) and sphingomyelins (SM d18:1/18:0) were significantly altered in the cortex of mice colonized by the microbiota obtained from aged donors. Transplantation of microbiota from old mice also modified the lipid class and fatty acid content in the liver. Finally, we found that the expression of several genes involved in MUFA and PUFA synthesis (, and ) was dysregulated in mice inoculated with an aged microbiota. In conclusion, our data suggest that changes in gut microbiota that are associated with aging can impact brain and liver lipid metabolisms. Lipid changes induced by an aged microbiota recapitulate some features of aging, thus pointing out the potential role of microbiota alterations in the age-related degradation of the health status.
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http://dx.doi.org/10.3389/fcimb.2019.00444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970973PMC
September 2020

Subretinal Drusenoid Deposits in the Elderly in a Population-Based Study (the Montrachet Study).

Invest Ophthalmol Vis Sci 2019 11;60(14):4838-4848

Department of Ophthalmology, University Hospital, Dijon, France.

Purpose: The aim of this study was to investigate the prevalence of subretinal drusenoid deposits (SDD) and to identify associated factors in an elderly population.

Methods: The participants of the population-based Montrachet study underwent an exhaustive ophthalmologic examination, including color fundus photography and macular spectral domain-optical coherence tomography (SD-OCT), coupled with infrared reflectance imaging. The presence of SDD and other age-related macular degeneration lesions, according to the European Eye Epidemiology SD-OCT classification of macular diseases, and subfoveal choroidal thickness were recorded. Moreover, the association of SDD and both clinical and demographic factors as well as plasma levels of vitamin E and lutein/zeaxanthin (L/Z) were analyzed.

Results: The mean age of patients was 82.3 ± 3.8 years and 62.7% were female. The prevalence of SDD was 18.1% (n = 205) in the subjects with at least one eye interpretable (n = 1135). In multivariate analysis, SDD was positively associated with increasing age (OR, 4.6; 95% CI, 2.8-7.7; P < 0.001 for subjects aged >85 years), female sex (OR, 1.7; 95% CI, 1.2-2.4; P = 0.005), and plasma L/Z level (OR, 1.2; 95% CI, 1.0-1.5; P = 0.039), and negatively associated with lipid-lowering drugs use (OR, 0.5; 95% CI, 0.3-0.9; P = 0.014 for statin medications) and subfoveal choroidal thickness (OR, 0.8; 95% CI, 0.7-0.9; P = 0.002).

Conclusions: The prevalence of SDD was high in subjects older than 75 years, more frequent in women, and was associated with a thinner choroid. The association with lipid-lowering drugs deserves further investigation.
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http://dx.doi.org/10.1167/iovs.19-27283DOI Listing
November 2019

Alteration of erythrocyte membrane polyunsaturated fatty acids in preterm newborns with retinopathy of prematurity.

Sci Rep 2019 05 28;9(1):7930. Epub 2019 May 28.

Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRA, Université Bourgogne Franche-Comté, Eye and Nutrition Research Group, Dijon, F-21000, France.

Extremely preterm infants are at high risk for retinopathy of prematurity (ROP), a potentially blinding disease characterized by abnormalities in retinal vascularization. Whereas animal studies revealed that n-3 polyunsaturated fatty acids (PUFAs) may be of benefit in preventing ROP, human studies conducted on preterm infants during the 1 weeks of life showed no association between blood n-3 PUFA bioavailability and ROP incidence and/or severity, probably because of the influence of nutrition on the lipid status of infants. In the OmegaROP prospective cohort study, we characterized the erythrocyte concentrations of PUFAs in preterm infants aged less than 29 weeks gestational age (GA) without any nutritional influence. We show that GA is positively associated with the erythrocyte n-6 to n-3 PUFA ratio, and particularly with the ratio of arachidonic acid (AA) to docosahexaenoic acid (DHA), in infants with ROP. A time-dependent accumulation of AA at the expense of DHA seems to occur in utero in erythrocytes of preterm infants who will develop ROP, thus reinforcing previous data on the beneficial properties of DHA on this disease. In addition, preliminary data on maternal erythrocyte membrane lipid concentrations suggest modifications in placental transfer of fatty acids. Documenting the erythrocyte AA to DHA ratio at birth in larger cohorts might be useful to set up new prognostic factors for ROP.
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http://dx.doi.org/10.1038/s41598-019-44476-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538605PMC
May 2019

Early impairments in the retina of rats fed with high fructose/high fat diet are associated with glucose metabolism deregulation but not dyslipidaemia.

Sci Rep 2019 04 12;9(1):5997. Epub 2019 Apr 12.

Eye and Nutrition Research Group, Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, INRA, CNRS, Université Bourgogne Franche-Comté, Dijon, France.

Way of life changes such as high consumption of processed foods rich in fat and sugar and sedentary lifestyle are associated with the increasing prevalence of metabolic syndrome (MetS) that affects about 35% in the American population. MetS is the main risk factor for diabetes mellitus, which is associated with vascular changes in the retina. However, the early consequences of MetS in the retina are not well described. We therefore aimed at characterizing the early effects of a high fructose and high fat diet (HFHF) on the function and structure of the rat retina, and evaluate the associations with metabolic changes. Brown Norway rats of 6 weeks of age were fed for 8 days, 5 weeks or 13 weeks with HFHF diet, or a standard chow. After only 4 weeks of this diet, rats exhibited a reduction in cone photoreceptor sensitivity to light. Moreover, we observed that MetS significantly exacerbated laser-induced choroidal neovascularization by 72% and 67% 2 weeks and 3 weeks post laser treatment, respectively. These retinal abnormalities were associated with deregulation of glucose metabolism but not lipid metabolism. These data showed retinal modifications in HFHF-induced MetS in the rat, at very early stage of the disease.
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http://dx.doi.org/10.1038/s41598-019-42528-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461688PMC
April 2019

Benefits of dimension reduction in penalized regression methods for high-dimensional grouped data: a case study in low sample size.

Bioinformatics 2019 10;35(19):3628-3634

Inserm, Bordeaux Population Health Research Center, Team LEHA, UMR 1219, University of Bordeaux, F-33000 Bordeaux, France.

Motivation: In some prediction analyses, predictors have a natural grouping structure and selecting predictors accounting for this additional information could be more effective for predicting the outcome accurately. Moreover, in a high dimension low sample size framework, obtaining a good predictive model becomes very challenging. The objective of this work was to investigate the benefits of dimension reduction in penalized regression methods, in terms of prediction performance and variable selection consistency, in high dimension low sample size data. Using two real datasets, we compared the performances of lasso, elastic net, group lasso, sparse group lasso, sparse partial least squares (PLS), group PLS and sparse group PLS.

Results: Considering dimension reduction in penalized regression methods improved the prediction accuracy. The sparse group PLS reached the lowest prediction error while consistently selecting a few predictors from a single group.

Availability And Implementation: R codes for the prediction methods are freely available at https://github.com/SoufianeAjana/Blisar.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz135DOI Listing
October 2019

Comprehensive study of rodent olfactory tissue lipid composition.

Prostaglandins Leukot Essent Fatty Acids 2018 04 23;131:32-43. Epub 2018 Mar 23.

Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRA, Université Bourgogne Franche-Comté, 9E Boulevard Jeanne d'Arc, F-21000 Dijon, France.

The peripheral olfactory tissue (OT) plays a primordial role in the detection and transduction of olfactory information. Recent proteomic and transcriptomic studies have provided valuable insight into proteins and RNAs expressed in this tissue. Paradoxically, there is little information regarding the lipid composition of mammalian OT. To delve further into this issue, using a set of complementary state-of-the-art techniques, we carried out a comprehensive analysis of OT lipid composition in rats and mice fed with standard diets. The results showed that phospholipids are largely predominant, the major classes being phosphatidylcholine and phosphatidylethanolamine. Two types of plasmalogens, plasmenyl-choline and plasmenyl-ethanolamine, as well as gangliosides were also detected. With the exception of sphingomyelin, substantial levels of n-3 polyunsaturated fatty acids, mainly docosahexaenoic acid (22:6n-3; DHA), were found in the different phospholipid classes. These findings demonstrate that the rodent OT shares several features in common with other neural tissues, such as the brain and retina.
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http://dx.doi.org/10.1016/j.plefa.2018.03.008DOI Listing
April 2018

Dry eye disease in the elderly in a French population-based study (the Montrachet study: Maculopathy, Optic Nerve, nuTRition, neurovAsCular and HEarT diseases): Prevalence and associated factors.

Ocul Surf 2018 01 20;16(1):112-119. Epub 2017 Sep 20.

Department of Ophthalmology, Dijon University Hospital, Dijon, France; Eye and Nutrition Research Group, CSGA, UMR 1324 INRA, 6265 CNRS, Burgundy University, Dijon, France.

Purpose: To estimate the prevalence of dry eye disease (DED) in the elderly and to describe systemic and ocular factors associated with DED in a population-based study, the Montrachet (Maculopathy Optic Nerve nuTRition neurovAsCular and HEarT diseases) study.

Methods: Dry eye symptoms were evaluated using the Ocular Surface Disease Index (OSDI) questionnaire. A self-reported history of dry eye symptoms and artificial tear use were also recorded. Every participant underwent an ophthalmic evaluation, which included the Schirmer test without anesthesia (Schirmer I), tear film breakup time (TFBUT) measurement, and fluorescein corneal staining evaluation.

Results: A total of 1045 subjects were included in the study. The mean age was 82.2 ± 3.8 years. The prevalence of DED according to symptoms, signs, or both was 34.4% [95% confidence interval ({CI)} 31.5-37.2], 34.5% [95% CI 31.6-37.3] and 13.0% [95% CI 10.9-15.0], respectively. Compared with men, women were more likely to self-report DED and artificial tear use, more often displayed an OSDI >22, and more often suffered from subjective and definite DED. In multivariate analysis, associated factors with definite DED were an educational level of short secondary school (to age 15 years), best-corrected visual acuity <20/60, dark iris color, systemic hypertension, and anxiolytic agent and antihistamine eye drop use.

Conclusion: Dry eye disease is a major ophthalmologic condition with a high prevalence among the elderly. We report well-documented factors associated with DED and new associations deserving further investigation.
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http://dx.doi.org/10.1016/j.jtos.2017.09.008DOI Listing
January 2018

Screening for Retinopathy of Prematurity: Insight into Optimizing Screening.

Ophthalmic Res 2018 27;59(4):228-234. Epub 2017 Jul 27.

Department of Ophthalmology, Dijon University Hospital, Dijon, France.

Purpose: To determine the factors influencing the time from preterm birth and retinopathy of prematurity (ROP) detection to optimize the timing of the initial screening.

Methods: This multicenter retrospective study enrolled preterm infants born before 32 weeks of gestational age (GA) and/or weighing less than 1,500 g between January 1, 2011, and December 31, 2015. ROP screening was performed using fundus photography with a wide-field camera. Population and follow-up characteristics were recorded.

Results: Among the 1,266 preterm infants observed, 795 were retained for analysis. One hundred seventy-four (21.6%) cases of ROP were detected with the first examination performed at 32.3 ± 1.6 weeks of postmenstrual age (PMA) and 5.4 ± 1.0 weeks of postnatal age (PNA). The first signs of ROP were detected at 34.0 ± 1.9 weeks of PMA and 7.2 ± 1.8 weeks of PNA, respectively. In the multivariate analysis, an older GA, a longer duration of mechanical ventilation, and a lower birth weight were correlated with a longer time between preterm birth and ROP detection (p < 0.0001, p < 0.0001, and p = 0.0359, respectively).

Conclusion: The first examination for ROP screening should be individualized to fit the first screening examination as closely as possible to the first signs of ROP in order to avoid unnecessary examinations without missing ROP.
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http://dx.doi.org/10.1159/000477622DOI Listing
June 2018

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease.

PLoS One 2017 2;12(6):e0178753. Epub 2017 Jun 2.

Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, Tuebingen, Germany.

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178753PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456345PMC
September 2017

Modulation of brain PUFA content in different experimental models of mice.

Prostaglandins Leukot Essent Fatty Acids 2016 11 30;114:1-10. Epub 2016 Sep 30.

Nutrition et Neurobiologie Intégrée, INRA UMR 1286, 33076 Bordeaux Cedex, Franceb University of Bordeaux, Bordeaux, France; Université de Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France.

The relative amounts of arachidonic acid (AA) and docosahexaenoic acid (DHA) govern the different functions of the brain. Their brain levels depend on structures considered, on fatty acid dietary supply and the age of animals. To have a better overview of the different models available in the literature we here compared the brain fatty acid composition in various mice models (C57BL/6J, CD1, Fat-1, SAMP8 mice) fed with different n-3 PUFA diets (deficient, balanced, enriched) in adults and aged animals. Our results demonstrated that brain AA and DHA content is 1) structure-dependent; 2) strain-specific; 3) differently affected by dietary approaches when compared to genetic model of PUFA modulation; 4) different in n-3 PUFA deficient aged C57BL6/J when compared to SAMP8 mouse model of aging. From these experiments, we highlight the difficulty to compare results obtained in different mouse models, different strains, different brain regions and different ages.
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http://dx.doi.org/10.1016/j.plefa.2016.09.003DOI Listing
November 2016

Rev-Erbα modulates retinal visual processing and behavioral responses to light.

FASEB J 2016 11 20;30(11):3690-3701. Epub 2016 Jul 20.

Department of Neurobiology of Rhythms, Centre National de la Recherche Scientifique, Unités Propres de Recherche 3212, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France;

The circadian clock is thought to adjust retinal sensitivity to ambient light levels, yet the involvement of specific clock genes is poorly understood. We explored the potential role of the nuclear receptor subfamily 1, group D, member 1 (REV-ERBα; or NR1D1) in this respect. In light-evoked behavioral tests, compared with wild-type littermates, Rev-Erbα mice showed enhanced negative masking at low light levels (0.1 lx). Rev-Erbα mouse retinas displayed significantly higher numbers of intrinsically photosensitive retinal ganglion cells (ipRGCs; 62% more compared with wild-type) and more intense melanopsin immunostaining of individual ipRGCs. In agreement with a pivotal role for melanopsin, negative masking at low light intensities was abolished in Rev-Erbα Opn4 (melanopsin gene) double-null mice. Rev-Erbα mice showed shortened latencies of both a and b electroretinogram waves, modified scotopic and photopic b-wave and scotopic threshold responses, and increased pupillary constriction, all of which suggested increased light sensitivity. However, wild-type and Rev-Erbα mice displayed no detectable differences by in vivo fundus imaging, retinal histology, or expression of cell type-specific markers for major retinal cell populations. We conclude that REV-ERBα plays a major role in retinal information processing, and we speculate that REV-ERBα and melanopsin set sensitivity levels of the rod-mediated ipRGC pathway to coordinate activity with ambient light.-Ait-Hmyed Hakkari, O., Acar, N., Savier, E., Spinnhirny, P., Bennis, M., Felder-Schmittbuhl, M.-P., Mendoza, J., Hicks, D. Rev-Erbα modulates retinal visual processing and behavioral responses to light.
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http://dx.doi.org/10.1096/fj.201600414RDOI Listing
November 2016

Spatial Distribution of Macular Pigment in an Elderly French Population: The Montrachet Study.

Invest Ophthalmol Vis Sci 2016 Aug;57(10):4469-4475

Centre des Sciences du Goût et de l'Alimentation, CNRS, INRA, University Bourgogne Franche-Comté, Dijon, France 3Dijon University Hospital, Ophthalmology Department, Dijon, France.

Purpose: We describe the spatial distribution and cross-sectional associations with physical and lifestyle attributes.

Methods: The participants of the Montrachet (Maculopathy Optic Nerve, nuTRition neurovAsCular and HEarT) study underwent an exhaustive ophthalmologic examination, including optical coherence tomography, to measure retinal thickness. The spatial distribution of macular pigment optical density (MPOD) defined as a ring-like, intermediate or no-ring pattern, was assessed by means of the two-wavelength autofluorescence technique. Blood samples were taken to measure plasma lutein and zeaxanthin using high performance liquid chromatography (HPLC).

Results: We studied 635 subjects with good-quality MPOD measurements. The mean age was 82.0 ± 3.4 years. A ring-like structure was found in 109 (17.2%) participants. Participants with a ring-like spatial distribution had a thinner macula in the central subfield (P < 0.001). In multivariate analysis, individuals never protecting themselves from sunlight and with dark iris color were less likely to present a ring-like than a no-ring spatial distribution (P = 0.033 and P = 0.013, respectively). Only in males were lutein plasma levels higher in ring-like and intermediate MPOD profiles than in no-ring structures (odds ratio [OR] = 1.59 for 100 additional μg; 95% confidence interval [CI] = 1.16-2.18 and OR = 1.64; 95% CI, 1.17-2.28).

Conclusions: In this population-based study, individuals never protecting themselves from sunlight, and with dark iris color and a thinner macula were less prone to displaying a ring-like MPOD spatial distribution.
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http://dx.doi.org/10.1167/iovs.16-19958DOI Listing
August 2016

Relationships of Macular Pigment Optical Density With Plasma Lutein, Zeaxanthin, and Diet in an Elderly Population: The Montrachet Study.

Invest Ophthalmol Vis Sci 2016 Mar;57(3):1160-7

INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, Dijon, France 3CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, Dijon, France 4Université Bourgogne Franche-Comté, Centre des Sciences du Goût et de l'Alimentation, Dijon, Fran.

Purpose: To investigate the association of macular pigment optical density (MPOD) with plasma lutein, zeaxanthin, and diet in an elderly population.

Methods: We conducted a population-based study, the Montrachet (Maculopathy Optic Nerve, nuTRition neurovAsCular, and HEarT disease) study, in subjects older than 75 years. The MPOD was measured by means of the two-wavelength autofluorescence technique. Plasma lutein and zeaxanthin were measured in fasting blood samples using HPLC. Food frequency consumption was assessed with self-reported food frequency questionnaires.

Results: Overall, 433 healthy participants (62.1% females) were included. Mean age was 82.0 ± 3.6 years. Mean MPOD at 0.5° eccentricity was 0.57 ± 0.25 density units (DU) and was higher in women than in men (0.59 ± 0.25 vs. 0.53 ± 0.25, P = 0.017). The MPOD was lower in alcohol consumers than in non-alcohol consumers (0.55 ± 0.25 vs. 0.61 ± 0.25, P = 0.016). Median plasma lutein and zeaxanthin levels were 281.4 μg/L and 20.0 μg/L, respectively, and were higher in women (P = 0.010 and P = 0.003, respectively). The MPOD was positively correlated with plasma lutein and zeaxanthin (r = 0.10, P = 0.030 and r = 0.11, P = 0.027, respectively). A higher consumption of squash was associated with higher plasma lutein and zeaxanthin. Adjusting for confounders and diet revealed that MPOD was weakly associated with plasma lutein in nonsmokers (β = 0.11, P = 0.021).

Conclusions: This study suggests that plasma lutein is associated with MPOD after taking into account potential confounding factors in an elderly population.
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http://dx.doi.org/10.1167/iovs.15-18007DOI Listing
March 2016

Early adaptive response of the retina to a pro-diabetogenic diet: Impairment of cone response and gene expression changes in high-fructose fed rats.

Exp Eye Res 2015 Jun 23;135:37-46. Epub 2015 Apr 23.

INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, Eye and Nutrition Research Group, F-21000 Dijon, France; CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; Université de Bourgogne, Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France. Electronic address:

The lack of plasticity of neurons to respond to dietary changes, such as high fat and high fructose diets, by modulating gene and protein expression has been associated with functional and behavioral impairments that can have detrimental consequences. The inhibition of high fat-induced rewiring of hypothalamic neurons induced obesity. Feeding rodents with high fructose is a recognized and widely used model to trigger obesity and metabolic syndrome. However the adaptive response of the retina to short term feeding with high fructose is poorly documented. We therefore aimed to characterize both the functional and gene expression changes in the neurosensory retina of Brown Norway rats fed during 3 and 8 days with a 60%-rich fructose diet (n = 16 per diet and per time point). Glucose, insulin, leptin, triacylglycerols, total cholesterol, HDL-cholesterol, LDL-cholesterol and fructosamine were quantified in plasma (n = 8 in each group). Functionality of the inner retina was studied using scotopic single flash electroretinography (n = 8 in each group) and the individual response of rod and cone photoreceptors was determined using 8.02 Hz Flicker electroretinography (n = 8 in each group). Analysis of gene expression in the neurosensory retina was performed by Affymetrix genechips, and confirmed by RT-qPCR (n = 6 in each group). Elevated glycemia (+13%), insulinemia (+83%), and leptinemia (+172%) was observed after 8 days of fructose feeding. The cone photoreceptor response was altered at day 8 in high fructose fed rats (Δ = 0.5 log unit of light stimulus intensity). Affymetrix analysis of gene expression highlighted significant modulation of the pathways of eIF2 signaling and endoplasmic reticulum stress, regulation of eIF4 and p70S6K signaling, as well as mTOR signaling and mitochondrial dysfunction. RT-qPCR analysis confirmed the down regulation of Crystallins, Npy, Nid1 and Optc genes after 3 days of fructose feeding, and up regulation of End2. Meanwhile, a trend towards an increased expression of αA- and αB-crystallin proteins was observed at day 8. Our results are consistent with early alterations of the functioning and gene expression in the retina in a pro diabetogenic environment.
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http://dx.doi.org/10.1016/j.exer.2015.04.012DOI Listing
June 2015

Pantethine Alters Lipid Composition and Cholesterol Content of Membrane Rafts, With Down-Regulation of CXCL12-Induced T Cell Migration.

J Cell Physiol 2015 Oct;230(10):2415-25

Aix Marseille University, CNRS, NICN UMR 7259, Marseille, France.

Pantethine, a natural low-molecular-weight thiol, shows a broad activity in a large range of essential cellular pathways. It has been long known as a hypolipidemic and hypocholesterolemic agent. We have recently shown that it exerts a neuroprotective action in mouse models of cerebral malaria and Parkinson's disease through multiple mechanisms. In the present study, we looked at its effects on membrane lipid rafts that serve as platforms for molecules engaged in cell activity, therefore providing a target against inappropriate cell response leading to a chronic inflammation. We found that pantethine-treated cells showed a significant change in raft fatty acid composition and cholesterol content, with ultimate downregulation of cell adhesion, CXCL12-driven chemotaxis, and transendothelial migration of various T cell types, including human Jurkat cell line and circulating effector T cells. The mechanisms involved include the alteration of the following: (i) CXCL12 binding to its target cells; (ii) membrane dynamics of CXCR4 and CXCR7, the two CXCL12 receptors; and (iii) cell redox status, a crucial determinant in the regulation of the chemokine system. In addition, we considered the linker for activation of T cells molecule to show that pantethine effects were associated with the displacement from the rafts of the acylated signaling molecules which had their palmitoylation level reduced.. In conclusion, the results presented here, together with previously published findings, indicate that due to its pleiotropic action, pantethine can downregulate the multifaceted process leading to pathogenic T cell activation and migration.
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http://dx.doi.org/10.1002/jcp.24971DOI Listing
October 2015

Incorporation of lutein and docosahexaenoic acid from dietary microalgae into the retina in quail.

Int J Food Sci Nutr 2015 Mar 6;66(2):222-9. Epub 2015 Feb 6.

Service de Nutrition, Institut Pasteur de Lille , Lille Cedex , France .

Lutein and docosahexaenoic acid (DHA) are associated with the prevention of age-related macular degeneration (AMD). Since microalgae are potent natural sources of these nutrients, their nutritional value should be evaluated based on the bioavailability of lutein and DHA for the retina via the plasmatic compartment. In this study, quail were fed for 5 months either with a diet supplemented or deprived with microalgae rich in lutein and DHA. In the microalgae-fed group, the retinal concentrations of lutein and zeaxanthin gradually increased whereas in plasma, these compounds started to increase from the first month of supplementation. We also observed a significant increase in retinal and plasmatic levels of DHA in the microalgae-fed group. In conclusion, the plasmatic and retinal contents of lutein and DHA were significantly increased in quail fed with lutein- and DHA-rich microalgae. Food fortification with microalgae may be an innovative way to increase lutein and DHA consumption in humans.
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http://dx.doi.org/10.3109/09637486.2014.971227DOI Listing
March 2015

Perinatal high-fat diet increases hippocampal vulnerability to the adverse effects of subsequent high-fat feeding.

Psychoneuroendocrinology 2015 Mar 15;53:82-93. Epub 2014 Dec 15.

INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, 33000 Bordeaux, France; Université de Bordeaux, Nutrition et Neurobiologie Intégrée, UMR 1286, 33000 Bordeaux, France. Electronic address:

Epidemiological observations report an increase in fat consumption associated with low intake of n-3 relative to n-6 polyunsaturated fatty acids (PUFAs) in women of childbearing age. However, the impact of these maternal feeding habits on cognitive function in the offspring is unknown. This study aims to investigate the impact of early exposure to a high-fat diet (HFD) with an unbalanced n-6/n-3 PUFAs ratio on hippocampal function in adult rats. Furthermore, we explored the effects of perinatal HFD combined with exposure to HFD after weaning. Dams were fed a control diet (C, 12% of energy from lipids, n-6/n-3 PUFAs ratio: 5) or HFD (HF, 39% of energy from lipids, n-6/n-3 PUFAs ratio: 39) throughout gestation and lactation. At weaning, offspring were placed either on control (C-C, HF-C) or high-fat (HF-HF) diets. In adulthood, hippocampus-dependent memory was assessed using the water-maze task and potential hippocampal alterations were determined by studying PUFA levels, gene expression, neurogenesis and astrocyte morphology. Perinatal HFD induced long-lasting metabolic alterations and some changes in gene expression in the hippocampus, but had no effect on memory. In contrast, spatial memory was impaired in animals exposed to HFD during the perinatal period and maintained on this diet. HF-HF rats also exhibited low n-3 and high n-6 PUFA levels, decreased neurogenesis and downregulated expression of several plasticity-related genes in the hippocampus. To determine the contribution of the perinatal diet to the memory deficits reported in HF-HF animals, an additional experiment was conducted in which rats were only exposed to HFD starting at weaning (C-HF). Interestingly, memory performance in this group was similar to controls. Overall, our results suggest that perinatal exposure to HFD with an unbalanced n-6/n-3 ratio sensitizes the offspring to the adverse effects of subsequent high-fat intake on hippocampal function.
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http://dx.doi.org/10.1016/j.psyneuen.2014.12.008DOI Listing
March 2015

Metabolic syndrome triggered by high-fructose diet favors choroidal neovascularization and impairs retinal light sensitivity in the rat.

PLoS One 2014 7;9(11):e112450. Epub 2014 Nov 7.

INRA, UMR 1324 Centre des Sciences du Goût et de l'Alimentation, Eye and Nutrition Research Group, Dijon, France; CNRS, UMR 6265 Centre des Sciences du Goût et de l'Alimentation, Dijon, France; Université de Bourgogne, Centre des Sciences du Goût et de l'Alimentation, Dijon, France.

Diabetic retinopathy and age-related macular degeneration are the leading causes of blindness in Western populations. Although it is a matter of controversy, large-scale population-based studies have reported increased prevalence of age-related macular degeneration in patients with diabetes or diabetic retinopathy. We hypothesized that metabolic syndrome, one of the major risk factors for type 2 diabetes, would represent a favorable environment for the development of choroidal neovascularization, the main complication of age-related macular degeneration. The fructose-fed rat was used as a model for metabolic syndrome in which choroidal neovascularization was induced by laser photocoagulation. Male Brown Norway rats were fed for 1, 3, and 6 months with a standard equilibrated chow diet or a 60%-rich fructose diet (n = 24 per time point). The animals expectedly developed significant body adiposity (+17%), liver steatosis at 3 and 6 months, hyperleptinemia at 1 and 3 months (two-fold increase) and hyperinsulinemia at 3 and 6 months (up to two-fold increase), but remained normoglycemic and normolipemic. The fructose-fed animals exhibited partial loss of rod sensitivity to light stimulus and reduced amplitude of oscillatory potentials at 6 months. Fructose-fed rats developed significantly more choroidal neovascularization at 14 and 21 days post-laser photocoagulation after 1 and 3 months of diet compared to animals fed the control diet. These results were consistent with infiltration/activation of phagocytic cells and up-regulation of pro-angiogenic gene expression such as Vegf and Leptin in the retina. Our data therefore suggested that metabolic syndrome would exacerbate the development of choroidal neovascularization in our experimental model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112450PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224482PMC
January 2016

Erythrocyte phospholipid and polyunsaturated fatty acid composition in diabetic retinopathy.

PLoS One 2014 4;9(9):e106912. Epub 2014 Sep 4.

INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, Dijon, France; CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, Dijon, France; Université de Bourgogne, UMR Centre des Sciences du Goût et de l'Alimentation, Dijon, France.

Background: Long chain polyunsaturated fatty acids (LCPUFAs) including docosahexaenoic acid and arachidonic acid are suspected to play a key role in the pathogenesis of diabetes. LCPUFAs are known to be preferentially concentrated in specific phospholipids termed as plasmalogens. This study was aimed to highlight potential changes in the metabolism of phospholipids, and particularly plasmalogens, and LCPUFAs at various stages of diabetic retinopathy in humans.

Methodology And Principal Findings: We performed lipidomic analyses on red blood cell membranes from controls and mainly type 2 diabetes mellitus patients with or without retinopathy. The fatty acid composition of erythrocytes was determined by gas chromatography and the phospholipid structure was determined by liquid chromatography equipped with an electrospray ionisation source and coupled with a tandem mass spectrometer (LC-ESI-MS/MS). A significant decrease in levels of docosahexaenoic acid and arachidonic acid in erythrocytes of diabetic patients with or without retinopathy was observed. The origin of this decrease was a loss of phosphatidyl-ethanolamine phospholipids esterified with these LCPUFAs. In diabetic patients without retinopathy, this change was balanced by an increase in the levels of several phosphatidyl-choline species. No influence of diabetes nor of diabetic retinopathy was observed on the concentrations of plasmalogen-type phospholipids.

Conclusions And Significance: Diabetes and diabetic retinopathy were associated with a reduction of erythrocyte LCPUFAs in phosphatidyl-ethanolamines. The increase of the amounts of phosphatidyl-choline species in erythrocytes of diabetic patients without diabetic retinopathy might be a compensatory mechanism for the loss of LC-PUFA-rich phosphatidyl-ethanolamines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106912PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154797PMC
December 2015

Plasmalogens in the retina: from occurrence in retinal cell membranes to potential involvement in pathophysiology of retinal diseases.

Biochimie 2014 Dec 12;107 Pt A:58-65. Epub 2014 Aug 12.

CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; Université de Bourgogne, UMR Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France. Electronic address:

Plasmalogens (Pls) represent a specific subclass of glycerophospholipids characterized by the presence of a vinyl-ether bond at the sn-1 position of glycerol. Pls are quantitatively important in membranes of neuronal tissues, including the brain and the retina, where they can represent until almost two-third of ethanolamine glycerophospholipids. They are considered as reservoirs of polyunsaturated fatty acids as several studies have shown that arachidonic and docosahexaenoic acids are preferentially esterified on Pls when compared to other glycerophospholipids. Reduced levels of Pls were observed in a number of neurodegenerative disorders such as glaucoma, the second leading cause of blindness worldwide. In a mouse model of Pls deficiency, "glaucoma-like" optic nerve abnormalities were observed as well as developmental defects in the eye. These included microphthalmia, dysgenesis of the anterior segment of the eye, and abnormalities in retinal vessel architecture. Several data from animal and in vitro studies suggest that Pls may be involved in the regulation of retinal vascular development through the release of polyunsaturated fatty acids by a calcium-independent phospholipase A2.
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http://dx.doi.org/10.1016/j.biochi.2014.07.023DOI Listing
December 2014

Involvement of plasmalogens in post-natal retinal vascular development.

PLoS One 2014 25;9(6):e101076. Epub 2014 Jun 25.

CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, Dijon, France; INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, Dijon, France; Université de Bourgogne, UMR Centre des Sciences du Goût et de l'Alimentation, Dijon, France.

Objective: Proper development of retinal blood vessels is essential to ensure sufficient oxygen and nutrient supplies to the retina. It was shown that polyunsaturated fatty acids (PUFAs) could modulate factors involved in tissue vascularization. A congenital deficiency in ether-phospholipids, also termed "plasmalogens", was shown to lead to abnormal ocular vascularization. Because plasmalogens are considered to be reservoirs of PUFAs, we wished to improve our understanding of the mechanisms by which plasmalogens regulate retinal vascular development and whether the release of PUFAs by calcium-independent phospholipase A2 (iPLA2) could be involved.

Methods And Results: By characterizing the cellular and molecular steps of retinal vascular development in a mouse model of plasmalogen deficiency, we demonstrated that plasmalogens modulate angiogenic processes during the early phases of retinal vascularization. They influence glial activity and primary astrocyte template formation, endothelial cell proliferation and retinal vessel outgrowth, and impact the expression of the genes involved in angiogenesis in the retina. These early defects led to a disorganized and dysfunctional retinal vascular network at adult age. By comparing these data to those obtained on a mouse model of retinal iPLA2 inhibition, we suggest that these processes may be mediated by PUFAs released from plasmalogens and further signalling through the angiopoietin/tie pathways.

Conclusions: These data suggest that plasmalogens play a crucial role in retinal vascularization processes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101076PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071069PMC
November 2015