FGF21 via mitochondrial lipid oxidation promotes physiological vascularization in a mouse model of Phase I ROP

Fu, Zhongjie; Lundgren, Pia; Pivodic, Aldina; Yagi, Hitomi; Harman, Jarrod C.; Yang, Jay; Ko, Minji; Neilsen, Katherine; Talukdar, Saswata; Hellström, Ann; Smith, Lois E H

doi:10.1007/s10456-023-09872-x

Cited by 6 publications

(1 citation statement)

References 62 publications

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“…In this model, supplementation of essential lipids and metabolic regulators lacking in premature infants improves retinal metabolism and neurovascular development. 2 , 25 , 36 Here, in the same Phase I ROP mouse model, we utilized targeted metabolomics to investigate the retinal metabolic responses to postnatal hyperglycemia, which can help optimize nutrient supply to preterm infants.…”

Section: Introductionmentioning

confidence: 99%

Postnatal hyperglycemia alters amino acid profile in retinas (model of Phase I ROP)

Harman,

Pivodic,

Nilsson

et al. 2023

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Section: Introductionmentioning

confidence: 99%

Postnatal hyperglycemia alters amino acid profile in retinas (model of Phase I ROP)

Harman,

Pivodic,

Nilsson

et al. 2023

iScience

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Systems levels analysis of lipid metabolism in oxygen-induced retinopathy

Singh

2023

Preprint

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Hyperoxia induces glutamine-fueled anaplerosis in the Muller cells, endothelial cells, and retinal explants. Anaplerosis takes away glutamine from the biosynthetic pathway to the energy-producing TCA cycle. This process depletes biosynthetic precursors from newly proliferating endothelial cells. The induction of anaplerosis in the hyperoxic retina is a compensatory response, either to decreased glycolysis or decreased flux from glycolysis to the TCA cycle. We hypothesized that by providing substrates that feed into TCA, we could reverse or prevent glutamine-fueled anaplerosis, thereby abating the glutamine wastage for energy generation. Using an oxygen-induced retinopathy (OIR) mouse model, we first compared the difference in fatty acid metabolism between OIR-resistant BALB/cByJ and OIR susceptible C57BL/6J strains to understand if these strains exhibit metabolic difference that protects BALB/cByJ from the hyperoxic conditions and prevents their vasculature in oxygen-induced retinopathy model. Based on our findings from the metabolic comparison between two mouse strains, we hypothesized that the medium-chain fatty acid, octanoate, can feed into the TCA and serve as an alternative energy source in response to hyperoxia. Our systems levels analysis of OIR model shows that the medium chain fatty acid can serve as an alternative source to feed TCA. We here, for the first time, demonstrate that the retina can use medium-chain fatty acid octanoate to replenish TCA in normoxic and at a higher rate in hyperoxic conditions.

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Protective Effects of Butyrate on Retinal Neovascularization in Preclinical Retinopathy of Prematurity Models

Oxenrider,

Bui,

Lester

et al. 2024

Preprint

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Retinopathy of prematurity (ROP) remains a leading cause of childhood blindness worldwide, necessitating new therapeutic strategies. Current interventions targeting advanced disease stages often fail to prevent long-term visual impairment. This study investigates the potential of sodium butyrate (NaB), an orally administered short-chain fatty acid, in preclinical models of ROP. Using the oxygen-induced retinopathy (OIR) mouse model, we demonstrate that daily oral NaB supplementation significantly protects against pathological angiogenesis, impacting not only vascular but also neuronal and microglial pathology in the inner retina. Notably, NaB shows efficacy in early-phase ROP intervention, as evidenced by studies in post-natal day 9 (P9) OIR mice and a novel hyperglycemia-associated retinopathy (HAR) model, which mimics the hyperglycemic conditions of many premature infants. These findings highlight NaB as a promising alternative or adjunct therapy to current anti-VEGF treatments, offering protection across multiple retinal cell types and stages of ROP development. The study underscores the need for further research to elucidate the specific mechanisms of NaB’s action, paving the way for its potential clinical application in ROP management. This research marks the first exploration of butyrate as a preventative and therapeutic agent for ROP, setting the stage for additional preclinical evaluations and optimization.HighlightsSodium butyrate (NaB) shows significant protection against pathological angiogenesis in the oxygen-induced retinopathy (OIR) mouse model.NaB impacts not only vascular but also neuronal and microglial pathology in the inner retina.The study highlights NaB’s potential as an early-phase intervention therapy for retinopathy of prematurity (ROP).This research is the first to investigate butyrate as a preventative and therapeutic agent for ROP.

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FGF21 via mitochondrial lipid oxidation promotes physiological vascularization in a mouse model of Phase I ROP

Cited by 6 publications

References 62 publications

Postnatal hyperglycemia alters amino acid profile in retinas (model of Phase I ROP)

Postnatal hyperglycemia alters amino acid profile in retinas (model of Phase I ROP)

Systems levels analysis of lipid metabolism in oxygen-induced retinopathy

Protective Effects of Butyrate on Retinal Neovascularization in Preclinical Retinopathy of Prematurity Models

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