Roles of adipose tissue metabolism on synthesis of photoreceptors outer segments and retinal senescence

Abstract

Purpose : Adipocytes have lipid droplets in their organelles specialized in fat storage. Free fatty-acids (FFAs) are released from lipid droplets to provide energy substrates. Since some FFAs such as docosahexaenoic acid cannot be synthesized de novo in mammals, adipose tissue is indispensable as a long-term depot of these FFAs. Considering that several FFAs have essential roles in retinal homeostasis, we hypothesized that adipocyte deficiency would promote retinal dysfunction and senescence. We investigated this hypothesis in two genetic mouse models where adipocytes are ablated.

Methods : C57BL/6J expressing an inducible diphtheria toxin receptor (Lox-Stop-Lox-ROSA-DTR) and adiponectin-Cre (DTR^ADQ) were used. DTR^ADQ mice were treated with diphtheria toxin intraperitoneally to eliminate adipocytes selectively. FAT-ATTAC (fat apoptosis through targeted activation of caspase 8) mice were treated with a dimerizer as another model to induce adipocyte apoptosis. Retinal responses were recorded by electroretinogram (ERG) using littermates that received the same treatments as controls. Transmission electron microscopy (TEM) was used to visualize photoreceptor structure. Senescence-associated (SA) β-galactosidase (Gal) staining was utilized to detect senescent cells which produce acid lysosomal β-Gal in retinal tissue.

Results : Both DTR^ADQ and FAT-ATTAC lost fat by postnatal adipocyte ablation. Fat-ablated mice demonstrated significantly decreased a- and b-wave amplitudes measured by ERG, indicating that adipocyte ablation induced retinal dysfunction. TEM images revealed that DTR^ADQ had sparse outer disc membrane compared to control suggesting an abnormality in outer segment synthesis. Furthermore, disc membranes at the base of photoreceptor outer segments were disorganized by adipocyte ablation. SA β-Gal staining revealed the increased level of β-Gal in the inner segment of photoreceptor in DTR^ADQmice, where lysosome localizes in photoreceptors.

Conclusions : Adipocytes play an essential role in retinal function and photoreceptor disc membrane synthesis. Ablation of adipocytes causes retinal dysfunction as measured by electrophysiology, and induces photoreceptor senescence.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

TEM image revealed DTR^ADQ mouse had sparse disc membrane in OS (arrow). Disc membrane was disorganized (arrowhead).

 

SA-β-Gal staining deteted increased SA-β-Gal activity in the IS of photoreceptors by adipocyte ablation (arrow).