ADIPOR1 is essential for vision and its RPE expression is lost in the Mfrprd6 mouse

Valentin M Sluch,Joanna Vrouvlianis,Shawn Hanks,Maura A Crowley,Junzheng Yang,Jorge Aranda,Dennis S Rice,Angela Banks,Alexandra M Hyman,Bo Chang,Barrett Leehy,John T Demirs,Chad E Bigelow,Chuanxi Xiang,Vanessa Davis,Hui Li

doi:10.1038/s41598-018-32579-9

Valentin M Sluch, Joanna Vrouvlianis + Show 14 more

Open Access

https://doi.org/10.1038/s41598-018-32579-9

Copy DOI

Journal: Scientific Reports	Publication Date: Sep 25, 2018
Citations: 36	License type: open-access

Affiliation: Novartis (United States), Jackson Laboratory

Abstract

The knockout (KO) of the adiponectin receptor 1 (AdipoR1) gene causes retinal degeneration. Here we report that ADIPOR1 protein is primarily found in the eye and brain with little expression in other tissues. Further analysis of AdipoR1 KO mice revealed that these animals exhibit early visual system abnormalities and are depleted of RHODOPSIN prior to pronounced photoreceptor death. A KO of AdipoR1 post-development either in photoreceptors or the retinal pigment epithelium (RPE) resulted in decreased expression of retinal proteins, establishing a role for ADIPOR1 in supporting vision in adulthood. Subsequent analysis of the Mfrprd6 mouse retina demonstrated that these mice are lacking ADIPOR1 in their RPE layer alone, suggesting that loss of ADIPOR1 drives retinal degeneration in this model. Moreover, we found elevated levels of IRBP in both the AdipoR1 KO and the Mfrprd6 models. The spatial distribution of IRBP was also abnormal. This dysregulation of IRBP hypothesizes a role for ADIPOR1 in retinoid metabolism.

Highlights

The knockout (KO) of the adiponectin receptor 1 (AdipoR1) gene causes retinal degeneration
It has been reported that adiponectin acts through binding to its receptors, adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2), respectively[1,2], and this relationship has been further propagated by studies that have shown that ablation of AdipoR1/AdipoR2 in mice led to the induction of insulin resistance and glucose intolerance[3]
While a number of publications on adiponectin receptor 1 (ADIPOR1) have relied on transcript levels to profile its expression[1,5,10], perhaps in part due to lacking a trustworthy antibody reagent, this dependency on transcript levels may be misleading since mRNA levels do not always correlate well with protein[11,12], especially across different tissues[13]

Summary

Introduction

The knockout (KO) of the adiponectin receptor 1 (AdipoR1) gene causes retinal degeneration. Subsequent analysis of the Mfrprd[6] mouse retina demonstrated that these mice are lacking ADIPOR1 in their RPE layer alone, suggesting that loss of ADIPOR1 drives retinal degeneration in this model. A contemporaneous study reported that AdipoR1 knockout (KO) mice did not develop insulin resistance while AdipoR2 KO mice were protected from developing this pathology when fed a high-fat diet[4] In addition to this discrepancy, it has recently been shown that the AdipoR1 KO developed retinal degeneration while the KO of adiponectin did not[5], suggesting that ADIPOR1 can definitively act independently of adiponectin. We profiled gene expression between AdipoR1 WT, heterozygous (HET), and KO animals and found that the interphotoreceptor retinoid-binding protein (IRBP, aka RBP3) was strongly upregulated in KO eyes prior to retinal degeneration, suggesting retinoid metabolism dysfunction. Subsequent analysis of Mfrprd[6] mouse eyes identified an IRBP increase in these mice prior to retinal degeneration akin to the AdipoR1 KO mice

Methods

Results

Conclusion