Dietary ω3polyunsaturated-fatty-acid decreases retinal neovascularization by adipose-ER-stress reduction to increase adiponectin

Abstract

Purpose: Retinopathy of prematurity (ROP) is a blinding disease in premature infants, with delayed retinal vascularization after preterm birth followed by compensatory but pathological vaso-proliferative ROP. Factors available in the third trimester of pregnancy in utero, and lacking after preterm birth such as omega-3 long-chain polyunsaturated fatty acid (ω-3LCPUFA), are associated with development of ROP. Dietary supplement of ω-3LCPUFA is protective in a mouse model of ROP. Our preliminary data show that white-adipose-tissue (WAT)-derived adiponectin (APN) is lower in serum from preterm infants with ROP vs. no ROP. We aimed to determine whether decreased APN levels in ROP are associated with deficiency of ω-3LCPUFA, and if APN mediates in part the protective effect of ω-3LCPUFA in ROP.

Methods: In the mouse model of oxygen-induced retinopathy (OIR), APN^-/- and wild-type (WT) mice were fed from birth isocaloric diets enriched with either ω-3 or ω-6LCPUFA. At P17 serum and WAT APN levels, retinal vaso-obliteration and neovascularization were quantified. Retinal APN and its receptors were examined with laser-captured microdissection; WAT ER stress markers and ER proteins were quantified.

Results: In OIR ω-3LCPUFA vs. ω-6 feed increased serum APN (ω-3: 5.8±1.4 vs. ω-6: 1.3±0.6μg/ml) and WAT APN levels (ω-3: 0.30±0.02 vs. ω-6: 0.23±0.02ng/μg) at P17. In WT the retinal vaso-protective effect of ω-3LCPUFA in OIR versus ω-6 feed (neovascular area ω-3/ω-6=0.3) was abolished in APN^-/- retinas (neovascular area ω-3/ω-6=0.9). APN receptors adipoR1, adipoR2 and T-cadherin were found in retinal neuronal layers and mRNA levels were higher in pathologic neovessels. ER stress was attenuated and ER proteins involved in packaging bioactive high molecular weight APN in WAT were elevated in ω-3LCPUFA vs. ω-6LCPUFA-fed mice.

Conclusions: Dietary ω-3LCPUFA may regulate production of APN through modulating ER stress in WAT. APN likely mediates in part the protective effects of ω-3 LCPUFA in OIR.