Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes

Asare-Bediako, Bright; Noothi, Sunil K.; Calzi, Sergio Li; Athmanathan, Baskaran; Vieira, Cristiano Pedrozo; Adu-Agyeiwaah, Yvonne; Dupont, Mariana; Jones, Bryce A.; Wang, Xiaoxin X.; Chakraborty, Dibyendu; Levi, Moshe; Nagareddy, Prabhakara R; Grant, Maria B.

doi:10.3390/cells9020464

Cited by 32 publications

(24 citation statements)

References 79 publications

(94 reference statements)

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“…The HFD-induced changes appeared to occur slower than those observed in T2DM models but were consistent with other retinopathy models, showing neural damage prior to vascular changes. This result falled in line with our findings 26 . We confirmed that a 32-week HFD (8 months) could induce both retinal vascularization and neurologic changes.…”

Section: Discussionsupporting

confidence: 94%

“…It was considered that retinal neovascularization occurs in mice after 7 months HFD feeding 27 . Bright Asare-Bediako et al 26 found that C57BL/6 mice fed with HFD showed a reduction in a-wave and b-wave amplitudes at 6 months and increased retinal nerve infarcts and vascular leakage, as well as reduced vascular density at 12 months. This evidence supported our findings.…”

Section: Discussionmentioning

confidence: 99%

“…The recent study by Bright Asare-Bediako revealed that the HFD mouse is a useful model for examining the effects of prediabetes and hypercholesterolemia on the retina 26 . Interestingly, the severity of retinopathy depended on HFD feeding duration 12 .…”

Section: Discussionmentioning

confidence: 99%

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Effects of high-fat diet and Apoe deficiency on retinal structure and function in mice

Cao

Guo

Wang

et al. 2020

Sci Rep

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To investigate the effects of a high-fat diet (HFD) and apolipoprotein E (Apoe) deficiency on retinal structure and function in mice. Apoe KO mice and wild-type C57BL/6J mice were given a low-fat diet (LFD) or a HFD for 32 weeks. Blood glucose, serum lipids, body weight and visceral fat weight were evaluated. Retinal sterol quantification was carried out by isotope dilution gas chromatography-mass spectrometry. The cholesterol metabolism related genes SCAP-SREBP expressions were detected by qRT-PCR. Retinal function was recorded using an electroretinogram. The thickness of each layer of the retina was measured by optical coherence tomography. Fundus fluorescein angiography was performed to detect retinal vasculature changes. Immunohistochemical staining was used to determine the expression of NF-κB, TNF-α and VEGFR2 in the retina among HFD, HFD Apoe−/−, LFD Apoe−/− and WT mice retinas. HFD feeding caused the mice to gain weight and develop hypercholesterinemia, while Apoe−/− abnormalities also affected blood lipid metabolism. Both HFD and Apoe deficiency elevated retinal cholesterol, especially in the HFD Apoe−/− mice. No up-regulated expression of SCAP-SREBP was observed as a negative regulator. Impaired retinal functions, thinning retinas and abnormal retinal vasculature were observed in the peripheral retinas of the HFD and Apoe−/− mice compared with those in the normal chow group, particularly in the HFD Apoe−/− mice. Moreover, the expression of NF-κB in the retinas of the HFD and Apoe−/− mice was increased, together with upregulated TNF-α mRNA levels and TNF-α expression in the layer of retinal ganglion cells of the peripheral retina. At the same time, the expression level of VEGFR2 was elevated in the intervention groups, most notably in HFD Apoe−/− mice. HFD or Apoe gene deletion had certain adverse effects on retinal function and structure, which were far below the combined factors and induced harm to the retina. Furthermore, HFD caused retinal ischemia and hypoxia. Additionally, Apoe abnormality increased susceptibility to ischemia. These changes upregulated NF-κB expression in ganglion cells and activated downstream TNF-α. Simultaneously, they activated VEGFR2, accelerating angiogenesis and vascular permeability. All of the aforementioned outcomes initiated inflammatory responses to trigger ganglion cell apoptosis and aggravate retinal neovascularization.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Effects of high-fat diet and Apoe deficiency on retinal structure and function in mice

Cao

Guo

Wang

et al. 2020

Sci Rep

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“…As indicated above, glucose and its products comprise one set of metabolites which can induce leukocyte activation while increased lipid, dyslipidemia, and particularly "bad" lipids indirectly activate leukocytes via cytokine release as a result of dysregulated sphingolipid metabolism (79). As for DR, the retinopathy in HFD-diet fed mice appears to be linked to increased adhesion molecule expression (187). The common denominator in this pathology seems therefore to be chronic, but dysregulated, leukocyte activation which has widespread effects on tissues generally and the retina in particular (Figure 9).…”

Section: Leukocyte Activation In Diabetes-what Is the Evidence?mentioning

confidence: 99%

The Role of Inflammation in Diabetic Retinopathy

2020

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Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5 + CD11b + monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.

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“…ERG studies Electroretinogram (ERG) studies were performed as previously described with assessment of photopic and s c o t o p i c r e s p o n s e s u s i n g U T A S B i g s h o t ( L K C Technologies, USA) [43].…”

Section: Visual Function Studiesmentioning

confidence: 99%

Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction

et al. 2021

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Aims/hypothesis Homo sapiens evolved under conditions of intermittent food availability and prolonged fasting between meals. Periods of fasting are important for recovery from meal-induced oxidative and metabolic stress, and tissue repair. Constant high energy-density food availability in present-day society contributes to the pathogenesis of chronic diseases, including diabetes and its complications, with intermittent fasting (IF) and energy restriction shown to improve metabolic health. We have previously demonstrated that IF prevents the development of diabetic retinopathy in a mouse model of type 2 diabetes (db/db); however the mechanisms of fasting-induced health benefits and fasting-induced risks for individuals with diabetes remain largely unknown. Sirtuin 1 (SIRT1), a nutrient-sensing deacetylase, is downregulated in diabetes. In this study, the effect of SIRT1 stimulation by IF, fasting-mimicking cell culture conditions (FMC) or pharmacological treatment using SRT1720 was evaluated on systemic and retinal metabolism, systemic and retinal inflammation and vascular and bone marrow damage. Methods The effects of IF were modelled in vivo using db/db mice and in vitro using bovine retinal endothelial cells or rat retinal neuroglial/precursor R28 cell line serum starved for 24 h. mRNA expression was analysed by quantitative PCR (qPCR). SIRT1 activity was measured via histone deacetylase activity assay. NR1H3 (also known as liver X receptor alpha [LXRα]) acetylation was measured via western blot analysis. Results IF increased Sirt1 mRNA expression in mouse liver and retina when compared with non-fasted animals. IF also increased SIRT1 activity eightfold in mouse retina while FMC increased SIRT1 activity and expression in retinal endothelial cells when compared with control. Sirt1 expression was also increased twofold in neuronal retina progenitor cells (R28) after FMC treatment. Moreover, FMC led to SIRT1-mediated LXRα deacetylation and subsequent 2.4-fold increase in activity, as measured by increased mRNA expression of the genes encoding ATP-binding cassette transporter (Abca1 and Abcg1). These changes were reduced when retinal endothelial cells expressing a constitutively acetylated LXRα mutant were tested. Increased SIRT1/LXR/ ABC-mediated cholesterol export resulted in decreased retinal endothelial cell cholesterol levels. Direct activation of SIRT1 by SRT1720 in db/db mice led to a twofold reduction of diabetes-induced inflammation in the retina and improved diabetes-induced visual function impairment, as measured by electroretinogram and optokinetic response. In the bone marrow, there was prevention of diabetes-induced myeloidosis and decreased inflammatory cytokine expression. Sandra S. Hammer and Cristiano P. Vieira contributed equally as first authors. Maria B. Grant and Julia V. Busik contributed equally as senior authors.

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Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes

Cited by 32 publications

References 79 publications

Effects of high-fat diet and Apoe deficiency on retinal structure and function in mice

Effects of high-fat diet and Apoe deficiency on retinal structure and function in mice

The Role of Inflammation in Diabetic Retinopathy

Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction

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