ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss

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.

Genetic Interaction between Mfrp and Adipor1 Mutations Affect Retinal Disease Phenotypes

“…Mutations in ADIPOR1 have been associated with retinitis pigmentosa [18,19] and agerelated macular degeneration [22]. While studies suggest that both ADIPOR1 and MFRP participate in docosahexaenoic acid (DHA, 22:6) enrichment [23] and lipid homeostasis in RPE and PR cells [24], there is still an incomplete understanding about the function of the individual proteins and their potential functional association and interaction that lead to similar disease phenotypes.…”

Ablation of Ctrp9, Ligand of AdipoR1, and Lower Number of Cone Photoreceptors in Mouse Retina

“…In contrast, ADIPOR1 was expressed in the retina as reported. 20 , 21 In vivo studies showed that the expression of CTRP9 transcripts is relatively restricted to adipose tissues. The adiponectin and CTRP9 transcripts are rarely expressed in the eye.…”

Sphingosine 1-Phosphate Mediates Adiponectin Receptor Signaling Essential For Lipid Homeostasis And Embryogenesis

“…Although AdipoR1-KO embryos/MEFs showed a relatively mild membrane defect phenotype, the consequences of AdipoR1 mutations can still be dramatic in the adult or in specific tissues. For instance, single amino acid mutation of AdipoR1 occurs in different forms of retinitis pigmentosa 57, 58 and AdipoR1-KO mice have a substantial degeneration of photoreceptors and visual impairment as early as 3 weeks of age that is due to the lack of PUFA in membrane phospholipids 54, 55 . This provides an independent confirmation that the AdipoR pathway is essential for membrane homeostasis, and shows that AdipoR1 has a specialized role in the maintenance of PUFA levels in the retina.…”