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

Abstract

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.

High-Fat Nutritional Challenge Reshapes Circadian Signatures in Murine Extraorbital Lacrimal Glands

“… 63 Several recent studies have shown that HFD significantly alters the rhythms of physiological function in the liver and brain. 20 , 44 , 46 , 69 , 82 Here, we show that HFD-induced metabolic stress also causes significant alterations in the immune-related transcriptome of lacrimal gland tissue. Moreover, an HFD changes the circadian phase and amplitude of trafficking of a variety of immune cells (mainly CD4 + and CD8 + T cells and neutrophils) to the lacrimal glands over a 24-hour cycle.…”

“… 15 – 18 Recent studies have demonstrated that HFD-fed mice showed various pathological alterations in retinal structure. 19 , 20 Mice fed an HFD for 10 days exhibited corneal dysfunction, including diminished corneal sensitivity and circadian activities (limbal neutrophil accumulation and epithelial cell division). 21 Following corneal abrasion, these mice showed delayed wound closure and nerve recovery and dysregulated leukocyte recruitment to the abraded cornea.…”

Chronic mild and acute severe glaucomatous neurodegeneration derived from silicone oil-induced ocular hypertension

“…To determine whether ischemia causes the severe inner retina degeneration in the ND group, we investigated flow in the inner retina blood vessels using fundus fluorescein angiography (FFA) 36 – 38 . We consistently found that blood flow was significantly delayed and decreased in ND retinas and to a lesser degree in LF retinas, whereas blood infiltration dynamics in HF retinas were similar to those in control retinas (Fig.…”

“…Indeed, ocular ischemia with inner retina damage and outer retina sparing has been reported in rats with acute high IOP elevation 42 – 45 . FFA is a diagnostic method for vascular deformation, non-perfusion and leakage, which can be used to evaluate the retinal blood supply 36 – 38 . It revealed significantly decreased blood flow in the inner retina of the ND group (Fig.…”

Effects of exercise on high-fat diet–induced non-alcoholic fatty liver disease and lipid metabolism in ApoE knockout mice

“…The pathogenesis of the ApoE knockout combined with a HFD also results in lipidosis and inflammation in lung tissue through the toll-like receptor 4 (TLR4) pathway [ 23 ]. Furthermore, Cao et al also demonstrated an increase in ischemia susceptibility, inflammation, ganglion cell apoptosis, and retinal neovascularization in the ApoE knockout when combined with the administration of a HFD [ 24 ]. The accumulation of oxidized-LDL on tendons can decrease the functionality and induce a proliferative and matrix-degrading phenotype in tenocytes under ApoE knockout conditions after administration of a HFD [ 25 ].…”