Abstract
Purpose :
Bisretinoid lipofuscin accumulates in retina with age. Bisretinoids form due to unchecked reactivity of vitamin A aldehyde and levels are known to reflect visual cycle kinetics; the difference between formation vs. photodegradative loss; and conditions underlying some forms of retinal disease. Otherwise modulators are little known. Here we sought to determine whether dysregulation of vitamin A in an experimental model of obesity associated with a high fat diet (HFD) can lead to increased formation of bisretinoids.
Methods :
Black (C57BL/6J) and albino (C57BL/6J2cj) wild type mice (all male) were raised either on a HFD (fat: 60% kcal from fat; from age 6 weeks) or a control diet (CD) (fat: 10% kcal from fat). Retinoids and bisretinoids were quantified by HPLC and UPLC with reference to authentic standards and non-invasive measurement of short wavelength fundus autofluorescence (488 nm; quantitative fundus autofluorescence, qAF) was performed. Rbp4 levels in mouse plasma were measured by ELISA.
Results :
In albino C57BL/6Jc2j mice fed a HFD from age 6 weeks to 12 months, final body weight was 30% higher than in mice fed a CD. At age 6 months, black C57BL/6J mice fed a HFD weighed 37% more than mice given a CD.
In C57BL/6J mice receiving the HFD there was a 2.2-fold increase in plasma all-trans-retinol (vitamin A) at age 14 weeks, a 17% increase in glucose and a 29% increase in retinol-binding protein 4 (Rbp4) relative to CD mice. In the plasma of HFD-fed C57BL/6J2cj mice (age 1 year), Rbp4 and retinol were also elevated relative to the CD.
Non-invasive measurement of bisretinoid by qAF revealed a 35% increase in the HFD-fed C57BL/6Jc2j mice (1.10.12, meanSD) as compared to CD-fed mice (0.80.1). The levels of A2E in the C57BL/6Jc2j HFD-fed mice were more than 2-fold greater than in the mice fed the CD and similar increases in A2GPE and A2DHPPE were also measured (for A2GPE, HFD: 11.42.8; control: 4.72.3). Quantitation of bisretinoids revealed that in 6 month old C57BL/6J mice the bisretinoids A2E, A2-DHP-PE and A2GPE were increased 44%, 36% and 3-fold, respectively. Diet-induced obese C57BL/6J mice at age 3 years also exhibited a 1.9 and 2.5-fold increase in A2E and A2-DHP-PE, respectively, relative to CD mice.
Conclusions :
A HFD leading to obesity in mice is associated with elevated plasma RBP4 and retinol, and elevated levels of bisretinoid lipofuscin in retina.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.