title: Dietary ω-3 polyunsaturated fatty acids decrease retinal neovascularization by adipose-endoplasmic reticulum stress reduction to increase adiponectin.
abstract: BACKGROUND
  Retinopathy of prematurity (ROP) is a vision-threatening disease in premature infants. Serum adiponectin (APN) concentrations positively correlate with postnatal growth and gestational age, important risk factors for ROP development. Dietary ω-3 (n-3) long-chain polyunsaturated fatty acids (ω-3 LCPUFAs) suppress ROP and oxygen-induced retinopathy (OIR) in a mouse model of human ROP, but the mechanism is not fully understood.
  
  
  OBJECTIVE
  We examined the role of APN in ROP development and whether circulating APN concentrations are increased by dietary ω-3 LCPUFAs to mediate the protective effect in ROP.
  
  
  METHODS
  Serum APN concentrations were correlated with ROP development and serum ω-3 LCPUFA concentrations in preterm infants. Mouse OIR was then used to determine whether ω-3 LCPUFA supplementation increases serum APN concentrations, which then suppress retinopathy.
  
  
  RESULTS
  We found that in preterm infants, low serum APN concentrations positively correlate with ROP, and serum APN concentrations positively correlate with serum ω-3 LCPUFA concentrations. In mouse OIR, serum total APN and bioactive high-molecular-weight APN concentrations are increased by ω-3 LCPUFA feed. White adipose tissue, where APN is produced and assembled in the endoplasmic reticulum, is the major source of serum APN. In mouse OIR, adipose endoplasmic reticulum stress is increased, and APN production is suppressed. ω-3 LCPUFA feed in mice increases APN production by reducing adipose endoplasmic reticulum stress markers. Dietary ω-3 LCPUFA suppression of neovascularization is reduced from 70% to 10% with APN deficiency. APN receptors localize in the retina, particularly to pathologic neovessels.
  
  
  CONCLUSIONS
  Our findings suggest that increasing APN by ω-3 LCPUFA supplementation in total parental nutrition for preterm infants may suppress ROP.
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Fu
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Chatarina A
authors.initials: CA
authors.lastname: Lofqvist
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Shao
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Joyal
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Christian G
authors.initials: CG
authors.lastname: Hurst
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Ricky Z
authors.initials: RZ
authors.lastname: Cui
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Lucy P
authors.initials: LP
authors.lastname: Evans
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Katherine
authors.initials: K
authors.lastname: Tian
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: John Paul
authors.initials: JP
authors.lastname: SanGiovanni
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: David
authors.initials: D
authors.lastname: Ley
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hansen Pupp
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Ann
authors.initials: A
authors.lastname: Hellstrom
authors.affiliation: From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA (ZF, ZS, YS, J-SJ, CGH, RZC, LPE, KT, JC, and LEHS); the Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (CAL and AH); the Department of Pediatrics, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden (DL and IHP); and National Eye Institute, Division of Epidemiology and Clinical Research Clinical Trials Branch, National Eye Institute, NIH, Bethesda, MD (JPS).
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
mesh_terms: D041721:3T3-L1 Cells; D052242:Adiponectin / Q000097:blood* / Q000172:deficiency; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D000831:Animals, Newborn / Q000097:blood; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011446:Prospective Studies; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D015861:Retinal Neovascularization / Q000097:blood / Q000188:drug therapy*; D012178:Retinopathy of Prematurity / Q000097:blood / Q000188:drug therapy
chemical_list: D052242:Adiponectin; D015525:Fatty Acids, Omega-3
keywords: adiponectin; endoplasmic reticulum stress; neovascularization; retinopathy of prematurity; white adipose tissue; ω-3 long-chain polyunsaturated fatty acids
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