Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment

Riccardo Natoli, Nilisha Fernando, Tess Dahlenburg, Haihan Jiao, Riemke Aggio-Bruce, Nigel L. Barnett, Juan Manuel Chao De La Barca, Guillaume Tcherkez, Pascal Reynier, Johnny Fang, Joshua A. Chu-Tan, Krisztina Valter, Jan Provis, Matt Rutar

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Abstract

Purpose: Systemic increases in reactive oxygen species, and their association with inflammation, have been proposed as an underlying mechanism linking obesity and age-related macular degeneration (AMD). Studies have found increased levels of oxidative stress biomarkers and inflammatory cytokines in obese individuals; however, the correlation between obesity and retinal inflammation has yet to be assessed. We used the leptin-deficient (ob/ob) mouse to further our understanding of the contribution of obesity to retinal oxidative stress and inflammation. Methods: Retinas from ob/ob mice were compared to age-matched wild-type controls for retinal function (electroretinography) and gene expression analysis of retinal stress (Gfap), oxidative stress (Gpx3 and Hmox1), and complement activation (C3, C2, Cfb, and Cfh). Oxidative stress was further quantified using a reactive oxygen species and reactive nitrogen species (ROS and RNS) assay. Retinal microglia and macrophage migration to the outer retina and complement activation were determined using immunohistochemistry for IBA1 and C3, respectively. Retinas and sera were used for metabolomic analysis using QTRAP mass spectrometry. Results: Retinal function was reduced in ob/ob mice, which correlated to changes in markers of retinal stress, oxidative stress, and inflammation. An increase in C3-expressing microglia and macrophages was detected in the outer retinas of the ob/ob mice, while gene expression studies showed increases in the complement activators (C2 and Cfb) and a decrease in a complement regulator (Cfh). The expression of several metabolites were altered in the ob/ob mice compared to the controls, with changes in polyunsaturated fatty acids (PUFAs) and branched-chain amino acids (BCAAs) detected. Conclusions: The results of this study indicate that oxidative stress, inflammation, complement activation, and lipid metabolites in the retinal environment are linked with obesity in ob/ob animals. Understanding the interplay between these components in the retina in obesity will help inform risk factor analysis for acquired retinal degenerations, including AMD.

Original languageEnglish
Pages (from-to)201-217
Number of pages17
JournalMolecular Vision
Volume24
Publication statusPublished - 7 Mar 2018
Externally publishedYes

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Complement Activation
Oxidative Stress
Obesity
Retina
Inflammation
Macular Degeneration
Microglia
Reactive Oxygen Species
Complement C2
Macrophages
Electroretinography
Gene Expression
Reactive Nitrogen Species
Branched Chain Amino Acids
Retinal Degeneration
Complement C3
Metabolomics
Leptin
Unsaturated Fatty Acids
Statistical Factor Analysis

Cite this

Natoli, R., Fernando, N., Dahlenburg, T., Jiao, H., Aggio-Bruce, R., Barnett, N. L., ... Rutar, M. (2018). Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment. Molecular Vision, 24, 201-217.
Natoli, Riccardo ; Fernando, Nilisha ; Dahlenburg, Tess ; Jiao, Haihan ; Aggio-Bruce, Riemke ; Barnett, Nigel L. ; De La Barca, Juan Manuel Chao ; Tcherkez, Guillaume ; Reynier, Pascal ; Fang, Johnny ; Chu-Tan, Joshua A. ; Valter, Krisztina ; Provis, Jan ; Rutar, Matt. / Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment. In: Molecular Vision. 2018 ; Vol. 24. pp. 201-217.
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title = "Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment",
abstract = "Purpose: Systemic increases in reactive oxygen species, and their association with inflammation, have been proposed as an underlying mechanism linking obesity and age-related macular degeneration (AMD). Studies have found increased levels of oxidative stress biomarkers and inflammatory cytokines in obese individuals; however, the correlation between obesity and retinal inflammation has yet to be assessed. We used the leptin-deficient (ob/ob) mouse to further our understanding of the contribution of obesity to retinal oxidative stress and inflammation. Methods: Retinas from ob/ob mice were compared to age-matched wild-type controls for retinal function (electroretinography) and gene expression analysis of retinal stress (Gfap), oxidative stress (Gpx3 and Hmox1), and complement activation (C3, C2, Cfb, and Cfh). Oxidative stress was further quantified using a reactive oxygen species and reactive nitrogen species (ROS and RNS) assay. Retinal microglia and macrophage migration to the outer retina and complement activation were determined using immunohistochemistry for IBA1 and C3, respectively. Retinas and sera were used for metabolomic analysis using QTRAP mass spectrometry. Results: Retinal function was reduced in ob/ob mice, which correlated to changes in markers of retinal stress, oxidative stress, and inflammation. An increase in C3-expressing microglia and macrophages was detected in the outer retinas of the ob/ob mice, while gene expression studies showed increases in the complement activators (C2 and Cfb) and a decrease in a complement regulator (Cfh). The expression of several metabolites were altered in the ob/ob mice compared to the controls, with changes in polyunsaturated fatty acids (PUFAs) and branched-chain amino acids (BCAAs) detected. Conclusions: The results of this study indicate that oxidative stress, inflammation, complement activation, and lipid metabolites in the retinal environment are linked with obesity in ob/ob animals. Understanding the interplay between these components in the retina in obesity will help inform risk factor analysis for acquired retinal degenerations, including AMD.",
author = "Riccardo Natoli and Nilisha Fernando and Tess Dahlenburg and Haihan Jiao and Riemke Aggio-Bruce and Barnett, {Nigel L.} and {De La Barca}, {Juan Manuel Chao} and Guillaume Tcherkez and Pascal Reynier and Johnny Fang and Chu-Tan, {Joshua A.} and Krisztina Valter and Jan Provis and Matt Rutar",
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Natoli, R, Fernando, N, Dahlenburg, T, Jiao, H, Aggio-Bruce, R, Barnett, NL, De La Barca, JMC, Tcherkez, G, Reynier, P, Fang, J, Chu-Tan, JA, Valter, K, Provis, J & Rutar, M 2018, 'Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment' Molecular Vision, vol. 24, pp. 201-217.

Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment. / Natoli, Riccardo; Fernando, Nilisha; Dahlenburg, Tess; Jiao, Haihan; Aggio-Bruce, Riemke; Barnett, Nigel L.; De La Barca, Juan Manuel Chao; Tcherkez, Guillaume; Reynier, Pascal; Fang, Johnny; Chu-Tan, Joshua A.; Valter, Krisztina; Provis, Jan; Rutar, Matt.

In: Molecular Vision, Vol. 24, 07.03.2018, p. 201-217.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment

AU - Natoli, Riccardo

AU - Fernando, Nilisha

AU - Dahlenburg, Tess

AU - Jiao, Haihan

AU - Aggio-Bruce, Riemke

AU - Barnett, Nigel L.

AU - De La Barca, Juan Manuel Chao

AU - Tcherkez, Guillaume

AU - Reynier, Pascal

AU - Fang, Johnny

AU - Chu-Tan, Joshua A.

AU - Valter, Krisztina

AU - Provis, Jan

AU - Rutar, Matt

PY - 2018/3/7

Y1 - 2018/3/7

N2 - Purpose: Systemic increases in reactive oxygen species, and their association with inflammation, have been proposed as an underlying mechanism linking obesity and age-related macular degeneration (AMD). Studies have found increased levels of oxidative stress biomarkers and inflammatory cytokines in obese individuals; however, the correlation between obesity and retinal inflammation has yet to be assessed. We used the leptin-deficient (ob/ob) mouse to further our understanding of the contribution of obesity to retinal oxidative stress and inflammation. Methods: Retinas from ob/ob mice were compared to age-matched wild-type controls for retinal function (electroretinography) and gene expression analysis of retinal stress (Gfap), oxidative stress (Gpx3 and Hmox1), and complement activation (C3, C2, Cfb, and Cfh). Oxidative stress was further quantified using a reactive oxygen species and reactive nitrogen species (ROS and RNS) assay. Retinal microglia and macrophage migration to the outer retina and complement activation were determined using immunohistochemistry for IBA1 and C3, respectively. Retinas and sera were used for metabolomic analysis using QTRAP mass spectrometry. Results: Retinal function was reduced in ob/ob mice, which correlated to changes in markers of retinal stress, oxidative stress, and inflammation. An increase in C3-expressing microglia and macrophages was detected in the outer retinas of the ob/ob mice, while gene expression studies showed increases in the complement activators (C2 and Cfb) and a decrease in a complement regulator (Cfh). The expression of several metabolites were altered in the ob/ob mice compared to the controls, with changes in polyunsaturated fatty acids (PUFAs) and branched-chain amino acids (BCAAs) detected. Conclusions: The results of this study indicate that oxidative stress, inflammation, complement activation, and lipid metabolites in the retinal environment are linked with obesity in ob/ob animals. Understanding the interplay between these components in the retina in obesity will help inform risk factor analysis for acquired retinal degenerations, including AMD.

AB - Purpose: Systemic increases in reactive oxygen species, and their association with inflammation, have been proposed as an underlying mechanism linking obesity and age-related macular degeneration (AMD). Studies have found increased levels of oxidative stress biomarkers and inflammatory cytokines in obese individuals; however, the correlation between obesity and retinal inflammation has yet to be assessed. We used the leptin-deficient (ob/ob) mouse to further our understanding of the contribution of obesity to retinal oxidative stress and inflammation. Methods: Retinas from ob/ob mice were compared to age-matched wild-type controls for retinal function (electroretinography) and gene expression analysis of retinal stress (Gfap), oxidative stress (Gpx3 and Hmox1), and complement activation (C3, C2, Cfb, and Cfh). Oxidative stress was further quantified using a reactive oxygen species and reactive nitrogen species (ROS and RNS) assay. Retinal microglia and macrophage migration to the outer retina and complement activation were determined using immunohistochemistry for IBA1 and C3, respectively. Retinas and sera were used for metabolomic analysis using QTRAP mass spectrometry. Results: Retinal function was reduced in ob/ob mice, which correlated to changes in markers of retinal stress, oxidative stress, and inflammation. An increase in C3-expressing microglia and macrophages was detected in the outer retinas of the ob/ob mice, while gene expression studies showed increases in the complement activators (C2 and Cfb) and a decrease in a complement regulator (Cfh). The expression of several metabolites were altered in the ob/ob mice compared to the controls, with changes in polyunsaturated fatty acids (PUFAs) and branched-chain amino acids (BCAAs) detected. Conclusions: The results of this study indicate that oxidative stress, inflammation, complement activation, and lipid metabolites in the retinal environment are linked with obesity in ob/ob animals. Understanding the interplay between these components in the retina in obesity will help inform risk factor analysis for acquired retinal degenerations, including AMD.

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JO - Molecular Vision

JF - Molecular Vision

SN - 1090-0535

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