Abstract
Lipid metabolism-related gene mutations can cause retinitis pigmentosa, a currently untreatable blinding disease resulting from progressive neurodegeneration of the retina. Here, we demonstrated the influence of adiponectin receptor 1 (ADIPOR1) deficiency in retinal neurodegeneration using Adipor1 knockout (KO) mice. Adipor1 mRNA was observed to be expressed in photoreceptors, predominately within the photoreceptor inner segment (PIS), and increased after birth during the development of the photoreceptor outer segments (POSs) where photons are received by the visual pigment, rhodopsin. At 3 weeks of age, visual function impairment, specifically photoreceptor dysfunction, as recorded by electroretinography (ERG), was evident in homozygous, but not heterozygous, Adipor1 KO mice. However, although photoreceptor loss was evident at 3 weeks of age and progressed until 10 weeks, the level of visual dysfunction was already substantial by 3 weeks, after which it was retained until 10 weeks of age. The rhodopsin mRNA levels had already decreased at 3 weeks, suggesting that reduced rhodopsin may have contributed to early visual loss. Moreover, inflammation and oxidative stress were induced in homozygous KO retinas. Prior to observation of photoreceptor loss via optical microscopy, electron microscopy revealed that POSs were present; however, they were misaligned and their lipid composition, including docosahexaenoic acid (DHA), which is critical in forming POSs, was impaired in the retina. Importantly, the expression of Elovl2, an elongase of very long chain fatty acids expressed in the PIS, was significantly reduced, and lipogenic genes, which are induced under conditions of reduced endogenous DHA synthesis, were increased in homozygous KO mice. The causal relationship between ADIPOR1 deficiency and Elovl2 repression, together with upregulation of lipogenic genes, was confirmed in vitro. Therefore, ADIPOR1 in the retina appears to be indispensable for ELOVL2 induction, which is likely required to supply sufficient DHA for appropriate photoreceptor function and survival.
Highlights
Recent progress in health research has revealed the significant impact of abnormal lipid metabolism in the pathogenesis of various diseases
We propose that adiponectin receptor 1 (ADIPOR1) deficiency affects the expression of Elovl[2], which contributes to docosahexaenoic acid (DHA) synthesis[18], and leads to insufficient levels of DHA in the retina, which likely contributes to retinal neural degeneration in Adipor[1] KO mice
As pigments that interfere with mRNA detection in the retinal pigment epithelium (RPE) are present in C57B/6 WT mice, albino BALB/c mice were analyzed to demonstrate Adipor[1] mRNA expression in the RPE (Fig. 1D)
Summary
Recent progress in health research has revealed the significant impact of abnormal lipid metabolism in the pathogenesis of various diseases. We focused on abnormal lipid metabolism in the retina, which is associated with adiponectin receptor 1 (ADIPOR1) deficiency. ADIPOR1 was initially described as an adiponectin receptor that affects systemic lipid and glucose metabolism[6,7,8]. More recently, it has Official journal of the Cell Death Differentiation Association. Osada et al Cell Death and Disease (2021)12:458 been described as a receptor for C1q tumor necrosis factor-related protein 9 (CTRP9), a newly discovered adipokine, which binds to SIRT1, a longevity factor[9]. In humans, ADIPOR1 mutation causes retinitis pigmentosa with or without systemic disorders, such as developmental and speech delays[10,11]
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