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• W1991970086 abstract "In clinical studies, postnatal weight gain is strongly associated with retinopathy of prematurity (ROP). However, animal studies are needed to investigate the pathophysiological mechanisms of how postnatal weight gain affects the severity of ROP. In the present study, we identify nutritional supply as one potent parameter that affects the extent of retinopathy in mice with identical birth weights and the same genetic background. Wild-type pups with poor postnatal nutrition and poor weight gain (PWG) exhibit a remarkably prolonged phase of retinopathy compared to medium weight gain or extensive weight gain pups. A high (r2 = 0.83) parabolic association between postnatal weight gain and oxygen-induced retinopathy severity is observed, as is a significantly prolonged phase of proliferative retinopathy in PWG pups (20 days) compared with extensive weight gain pups (6 days). The extended retinopathy is concomitant with prolonged overexpression of retinal vascular endothelial growth factor in PWG pups. Importantly, PWG pups show low serum levels of nonfasting glucose, insulin, and insulin-like growth factor-1 as well as high levels of ghrelin in the early postoxygen-induced retinopathy phase, a combination indicative of poor metabolic supply. These differences translate into visual deficits in adult PWG mice, as demonstrated by impaired bipolar and proximal neuronal function. Together, these results provide evidence for a pathophysiological correlation between poor postnatal nutritional supply, slow weight gain, prolonged retinal vascular endothelial growth factor overexpression, protracted retinopathy, and reduced final visual outcome. In clinical studies, postnatal weight gain is strongly associated with retinopathy of prematurity (ROP). However, animal studies are needed to investigate the pathophysiological mechanisms of how postnatal weight gain affects the severity of ROP. In the present study, we identify nutritional supply as one potent parameter that affects the extent of retinopathy in mice with identical birth weights and the same genetic background. Wild-type pups with poor postnatal nutrition and poor weight gain (PWG) exhibit a remarkably prolonged phase of retinopathy compared to medium weight gain or extensive weight gain pups. A high (r2 = 0.83) parabolic association between postnatal weight gain and oxygen-induced retinopathy severity is observed, as is a significantly prolonged phase of proliferative retinopathy in PWG pups (20 days) compared with extensive weight gain pups (6 days). The extended retinopathy is concomitant with prolonged overexpression of retinal vascular endothelial growth factor in PWG pups. Importantly, PWG pups show low serum levels of nonfasting glucose, insulin, and insulin-like growth factor-1 as well as high levels of ghrelin in the early postoxygen-induced retinopathy phase, a combination indicative of poor metabolic supply. These differences translate into visual deficits in adult PWG mice, as demonstrated by impaired bipolar and proximal neuronal function. Together, these results provide evidence for a pathophysiological correlation between poor postnatal nutritional supply, slow weight gain, prolonged retinal vascular endothelial growth factor overexpression, protracted retinopathy, and reduced final visual outcome. Although retinopathy of prematurity (ROP) in human infants develops postnatally, birth weight and short gestational age at birth have long been considered the most potent predictors for ROP.1Saugstad OD Oxygen and retinopathy of prematurity.J Perinatol. 2006; 26 (discussion S63–S44): S46-S50Crossref PubMed Scopus (82) Google Scholar Postnatal oxygen incubation was recognized as an additional risk factor, but with modern perinatal care, the detrimental effects of oxygen incubation have been minimized.2Sears JE Pietz J Sonnie C Dolcini D Hoppe G A change in oxygen supplementation can decrease the incidence of retinopathy of prematurity.Ophthalmology. 2009; 116: 513-518Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar Postnatal weight gain, in contrast, has only recently received growing attention among clinicians as an independent, postnatal variable that can reliably predict ROP.3Hellstrom A Hard AL Engstrom E Niklasson A Andersson E Smith L Lofqvist C Early weight gain predicts retinopathy in preterm infants: new, simple, efficient approach to screening.Pediatrics. 2009; 123: e638-e645Crossref PubMed Scopus (178) Google Scholar, 4Fortes Filho JB Bonomo PP Maia M Procianoy RS Weight gain measured at 6 weeks after birth as a predictor for severe retinopathy of prematurity: study with 317 very low birth weight preterm babies.Graefes Arch Clin Exp Ophthalmol. 2009; 247: 831-836Crossref PubMed Scopus (70) Google Scholar, 5Hellstrom A Ley D Hansen-Pupp I Niklasson A Smith L Lofqvist C Hard AL New insights into the development of retinopathy of prematurity: importance of early weight gain.Acta Paediatr. 2010; 99: 502-508Crossref PubMed Scopus (67) Google Scholar, 6Lofqvist C Andersson E Sigurdsson J Engstrom E Hard AL Niklasson A Smith LE Hellstrom A Longitudinal postnatal weight and insulin-like growth factor I measurements in the prediction of retinopathy of prematurity.Arch Ophthalmol. 2006; 124: 1711-1718Crossref PubMed Scopus (218) Google Scholar, 7Lofqvist C Hansen-Pupp I Andersson E Holm K Smith LE Ley D Hellstrom A Validation of a new retinopathy of prematurity screening method monitoring longitudinal postnatal weight and insulinlike growth factor I.Arch Ophthalmol. 2009; 127: 622-627Crossref PubMed Scopus (136) Google Scholar To understand the pathophysiology of how postnatal weight gain affects ROP, we must identify and investigate the individual components of postnatal weight gain that can have an impact on pathological angiogenesis in the developing retina. This can best be achieved in the established animal models of oxygen-induced retinopathy (OIR), where the hallmarks of human ROP are replicated and retinal neovascularization (NV) can be studied in a well controlled setting.8Smith LE Wesolowski E McLellan A Kostyk SK D'Amato R Sullivan R D'Amore PA Oxygen-induced retinopathy in the mouse.Invest Ophthalmol Vis Sci. 1994; 35: 101-111PubMed Google Scholar, 9Stahl A Connor KM Sapieha P Chen J Dennison RJ Krah NM Seaward MR Willett KL Aderman CM Guerin KI Hua J Lofqvist C Hellstrom A Smith LE The mouse retina as an angiogenesis model.Invest Ophthalmol Vis Sci. 2010; 51: 2813-2826Crossref PubMed Scopus (441) Google Scholar Similar to human ROP where the prematurely born infant is initially exposed to an environment that is relatively hyperoxic in comparison to the intrauterine environment,10Singer D Muhlfeld C Perinatal adaptation in mammals: the impact of metabolic rate.Comp Biochem Physiol A Mol Integr Physiol. 2007; 148: 780-784Crossref PubMed Scopus (46) Google Scholar the OIR model exposes mouse pups to hyperoxic conditions (75% O2 from postnatal day (P)7 to P12) to induce vaso-obliteration (VO) of immature retinal capillaries. Also analogous to human ROP, where the second phase is characterized by tissue hypoxia of the avascular retina and subsequent up-regulation of proangiogenic factors, mouse pups in the second phase of the OIR model (P12–P17) reactivate retinal angiogenesis, leading to both functional vessel regrowth as well as pathological retinal NV.8Smith LE Wesolowski E McLellan A Kostyk SK D'Amato R Sullivan R D'Amore PA Oxygen-induced retinopathy in the mouse.Invest Ophthalmol Vis Sci. 1994; 35: 101-111PubMed Google Scholar, 11Connor KM Krah NM Dennison RJ Aderman CM Chen J Guerin KI Sapieha P Stahl A Willett KL Smith LE Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis.Nat Protoc. 2009; 4: 1565-1573Crossref PubMed Scopus (479) Google Scholar Our results demonstrate that mice with poor postnatal weight gain (PWG) exhibit a delayed and remarkably prolonged phase of retinopathy compared with medium weight gain (MWG) or extensive weight gain (EWG) pups. Associated with the differences in postnatal weight gain are distinct patterns for serum markers of metabolic supply. Increasing metabolic supply in litter-matched experiments isolates postnatal nutritional intake as one potent parameter affecting both postnatal weight gain and the severity of ROP. Locally, in the retina, these differences in nutritional supply and weight gain translate into distinct patterns of vascular endothelial growth factor (VEGF) expression: In PWG pups, retinal VEGF overexpression is significantly prolonged compared with MWG or EWG pups, matching the prolonged time course of active retinopathy in these pups. This prolongation of retinopathy, in turn, results in electroretinographic (ERG) deficits in adult PWG mice, demonstrating that insufficient nutritional supply and poor postnatal weight gain in association with changes in retinal VEGF expression profoundly alter the course and outcome of ROP. All studies adhered to the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research and were approved by the Children's Hospital Boston Animal Care and Use Committee. C57BL/6 (Taconic stock no. B6-F, B6-M) were purchased from Taconic Farms (Germantown, NY) and used for all experiments. The deciding factor for grouping the mice was weight at P17 (PWG <5 g, MWG 5–7.5 g and EWG >7.5 g at P17). Weights collected before P17 were entered retrospectively after the group assignment was decided based on P17 weights. Not all EWG mice were kept with two dams. We observed spontaneous EWG also in pups with one dam and small litter size. Mice were exposed to 75% oxygen from P7 to P12. On return to room air, hypoxia-driven NV is initiated and becomes morphologically visible from P15 onward.8Smith LE Wesolowski E McLellan A Kostyk SK D'Amato R Sullivan R D'Amore PA Oxygen-induced retinopathy in the mouse.Invest Ophthalmol Vis Sci. 1994; 35: 101-111PubMed Google Scholar, 11Connor KM Krah NM Dennison RJ Aderman CM Chen J Guerin KI Sapieha P Stahl A Willett KL Smith LE Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis.Nat Protoc. 2009; 4: 1565-1573Crossref PubMed Scopus (479) Google Scholar To quantify NV and VO, at age of analysis, mice were given a lethal dose of Avertin, and eyes were enucleated and fixed in 4% paraformaldehyde for 1 hour at room temperature. Retinas were dissected and stained overnight with fluoresceinated Isolectin B4 (Alexa Fluor 594 – I21413; Molecular Probes, Eugene, OR) in 1 mmol/L CaCl2 in PBS. Lectin-stained retinas were flat-mounted with the photoreceptor side down, and 20 images of each flat-mounted retina were obtained at 5× magnification on a Zeiss AxioObserver.Z1 microscope and merged to form one image using AxioVision 4.6.3.0 software. VO was quantified by manually outlining the avascular area using Adobe Photoshop.11Connor KM Krah NM Dennison RJ Aderman CM Chen J Guerin KI Sapieha P Stahl A Willett KL Smith LE Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis.Nat Protoc. 2009; 4: 1565-1573Crossref PubMed Scopus (479) Google Scholar NV was analyzed using the SWIFT_NV method.12Stahl A Connor KM Sapieha P Willett KL Krah NM Dennison RJ Chen J Guerin KI Smith LE Computer-aided quantification of retinal neovascularization.Angiogenesis. 2009; 12: 297-301Crossref PubMed Scopus (117) Google Scholar SWIFT_NV consists of a set of macros that was developed to run on the National Institutes of Health's free ImageJ platform. In brief, SWIFT_NV isolates the red channel from a lectin-stained retinal whole mount, divides the image into four quadrants, and removes background fluorescence to allow for the NV structures to stand out clearly against the background fluorescence of normal vessels. Using a slide bar to either increase or decrease a particular quadrant's fluorescence threshold, the SWIFT_NV user designates a threshold that marks NV structures but not normal vessels to each quadrant. After setting the appropriate threshold, artifacts like remaining hyaloid vessels, cellular debris, or hyperfluorescent retinal edges can be manually marked and excluded from quantification. SWIFT_NV then analyzes all pixels in the image that lie above the chosen intensity threshold and are part of an object that has a defined minimum size. By setting this fixed cut-off in object size, small artifacts like vessel branch points are automatically removed. After measuring all four quadrants, SWIFT_NV creates a composite from all four NV quadrants and calculates the total NV pixel number.12Stahl A Connor KM Sapieha P Willett KL Krah NM Dennison RJ Chen J Guerin KI Smith LE Computer-aided quantification of retinal neovascularization.Angiogenesis. 2009; 12: 297-301Crossref PubMed Scopus (117) Google Scholar Blood was obtained from mice at the indicated postnatal days. Care was taken to obtain blood samples at the same hour of the day to control for circadian fluctuations.13Emberson JR Whincup PH Walker M Thomas M Alberti KG Biochemical measures in a population-based study: effect of fasting duration and time of day.Ann Clin Biochem. 2002; 39: 493-501Crossref PubMed Scopus (80) Google Scholar Blood glucose was measured using Accu-Chek (Roche, Mannheim, Germany). The remaining blood was allowed to clot at room-temperature for 2 hours. After centrifugation (20 minutes at 2000 × g), the serum was collected, frozen at −80°C, and later analyzed using Insulin ELISAs (Crystal Chem.), insulin-like growth factor (IGF)-1 ELISAs (R&D Systems, Minneapolis, MN), and ghrelin ELISAs (Millipore, Bedford, MA) following the manufacturers' instructions. Retinas were isolated at the indicated time points, frozen in liquid nitrogen, and stored at −80°C. For gene expression analysis, RNA was isolated using tissue homogenizer columns and RNA mini columns (Qiagen, Chatsworth, CA). Samples were treated with DNase I (Qiagen, Chatsworth, CA) to remove any contaminating genomic DNA and converted into cDNA using reverse transcriptase (Invitrogen, Carlsbad, CA). PCR primers targeting VEGF and an unchanging control gene, cyclophilin A, were designed using Primer Bank and National Center for Biotechnology Information Primer Blast software (sequences available on request). Quantitative analysis of gene expression was performed using an ABI Prism 7700 Sequence Detection System with the SYBR Green Master Mix kit. Gene expression was calculated relative to cyclophilin A using the ΔcT method. For protein analysis, retinas were homogenized and sonicated in 1% Nonidet P-40 in PBS (Roche Diagnostics) containing an array of phosphatase and protease inhibitors (Sigma-Aldrich, St. Louis, MO). Samples were normalized using a bicinchoninic acid assay (Pierce, Rockford, IL) and quantified for VEGF protein using a commercially available ELISA system (R&D Systems). Cryosections were prepared at 12-μm thickness, and staining was performed following standard protocols using H&E reagents from Sigma-Aldrich. Retinas from P70 mice were obtained, and lectin-stained flat-mounts prepared as described above. Using ImageJ's threshold algorithm, the area covered by lectin-positive vessels was quantified relative to the whole retinal area. Data are presented as the mean + SD. Retinal function was assessed at P70. Mice were presented with a series of “green” flashes of doubling intensity from 0.000500 to 2.05 cd · s · m−2 and then “white” flashes from 8.19 to 1050 cd · s · m−2; the white flash was found to be half as efficient (per cd · s · m−2) at eliciting a b-wave.14Akula JD Mocko JA Benador IY Hansen RM Favazza TL Vyhovsky TC Fulton AB The neurovascular relation in oxygen-induced retinopathy.Mol Vis. 2008; 14: 2499-2508PubMed Google Scholar The response to a 1.024 cd · s · m−2 light flickering at 8 Hz was also studied. The amplitude (RmP3) and sensitivity (S) of the rod photoresponse (PIII) were estimated from the ERG by ensemble fit of the parameters of the Hood and Birch15Hood DC Birch DG A computational model of the amplitude and implicit time of the b-wave of the human ERG.Vis Neurosci. 1992; 8: 107-126Crossref PubMed Scopus (150) Google Scholar formulation of the Lamb and Pugh16Lamb TD Pugh Jr, EN A quantitative account of the activation steps involved in phototransduction in amphibian photoreceptors.J Physiol. 1992; 449: 719-758Crossref PubMed Scopus (505) Google Scholar, 17Pugh Jr, EN Lamb TD Amplification and kinetics of the activation steps in phototransduction.Biochim Biophys Acta. 1993; 1141: 111-149Crossref PubMed Scopus (518) Google Scholar model of the biochemical processes involved in the activation of phototransduction to the a-waves elicited by the white flashes. “Ensemble” means the mean square error across all included traces was minimized simultaneously. Fitting of the model was restricted to the leading edge of the a-wave. The amplitude (RmP2) and sensitivity (Log kP2) of the bipolar cell response was derived by fit of the Naka-Rushton function to the response versus intensity relationship of PII, the putatively pure postreceptor potential obtained by subtraction of PIII from the intact ERG waveform. The oscillatory potentials (OPs) were analyzed, ensemble, in the frequency domain following discreet Fourier transform of the first 100 ms of PII.18Akula JD Mocko JA Moskowitz A Hansen RM Fulton AB The oscillatory potentials of the dark-adapted electroretinogram in retinopathy of prematurity.Invest Ophthalmol Vis Sci. 2007; 48: 5788-5797Crossref PubMed Scopus (55) Google Scholar The saturating energy in the OPs (Em) was derived, similarly to RmP2, by fit of the Michaelis-Menton equation to the response versus intensity relationship of OP energy. The trough-to-peak amplitude of the flicker response (R8) was also measured. All data were described as the log change from the EWG group; by expressing the data in log values, changes in observations of fixed proportion, either up or down, become linear, consistent with a constant fraction for physiologically meaningful changes in parameter values. Differences between groups were detected using analysis of variance corrected for multiple testing with Tukey-Kramer honestly significant difference. Comparisons between two groups were performed using unpaired Student's t-test. Inherent differences in weight gain in pups during the OIR model have been noted before, both in mice and rats.19Holmes JM Duffner LA The effect of postnatal growth retardation on abnormal neovascularization in the oxygen exposed neonatal rat.Curr Eye Res. 1996; 15: 403-409Crossref PubMed Scopus (71) Google Scholar, 20Vanhaesebrouck S Daniels H Moons L Vanhole C Carmeliet P De Zegher F Oxygen-induced retinopathy in mice: amplification by neonatal IGF-I deficit and attenuation by IGF-I administration.Pediatr Res. 2009; 65: 307-310Crossref PubMed Scopus (66) Google Scholar However, a stringent analysis of the correlation between weight gain and severity of retinopathy in rodents during OIR remained to be performed. We therefore initiated our study by screening a cohort of 15 litters of C57BL/6 wild-type mice undergoing OIR for correlations between postnatal body weight and extent of NV at P17, the standard time point to investigate NV in the OIR mouse model.8Smith LE Wesolowski E McLellan A Kostyk SK D'Amato R Sullivan R D'Amore PA Oxygen-induced retinopathy in the mouse.Invest Ophthalmol Vis Sci. 1994; 35: 101-111PubMed Google Scholar Our results revealed a parabolic correlation between body weight and extent of NV at P17 (r2 = 0.83; Figure 1A). Mice with body weights between 5 and 7.5 g at P17 displayed the highest amount of NV, while mice with either less than 5 g or more than 7.5 g body weight at P17 showed significantly lower severity of NV. We next asked if the difference in body weight at P17 was due to different birth weights or differences in postnatal weight gain. On the basis of the three different weight clusters observed in Figure 1A, three distinct groups were defined and followed from P1 to P21: P17 body weight below 5 g (group 1), P17 body weight between 5 and 7.5 g (group 2), and P17 body weight above 7.5 g (group 3). Longitudinal weight data collected from a total of 226 C57BL/6 wild-type mice revealed that these three groups do not differ in weights at P1 (Figure 1B). It was thus postnatal weight gain that results in the observed differences at P17. On the basis of this result, group 1 was labeled PWG (<5 g at P17), group 2 MWG (5–7.5 g at P17), and group 3 EWG (>7.5 g at P17). Starting from identical weights at P1, EWG pups are characterized by significantly higher weights compared with MWG, PWG, and the normoxic control group by P7. The MWG group closely follows the normoxic growth curve up to and throughout the hyperoxic incubation period from P7–P12. However, after return to room air at P12, MWG pups display a marked slow-down in weight gain compared with normoxic controls that is only corrected by P19. In a strikingly different pattern, PWG pups show slower weight gain during hyperoxic incubation (P7–P12) followed by a 14% weight loss during the early hypoxic phase and significantly slower growth rates throughout the whole observation period. To investigate how these different postnatal weight gain patterns correlate with retinopathy, we analyzed NV and VO on a total of 216 retinas from P15 to P35 (Figure 1, C and D). Both EWG and MWG pups exhibit a similar time course in the evolution and regression of NV, with maximal severity at P17 and relatively rapid regression thereafter (Figure 1C). However, peak severity of NV is significantly lower in EWG mice compared with MWG (5.6 ± 0.9 versus 8.5 ± 0.3%NV at P17; P < 0.0001), and resolution of NV is correspondingly found earlier in EWG mice (P21 versus P25). Different from both EWG and MWG mice, PWG pups show a delayed onset of NV with lower magnitude at P17 (3.9 ± 0.2%NV; P < 10−5). However, in contrast to EWG and MWG pups, NV severity in PWG pups keeps rising beyond P17, resulting in a prolonged NV peak from P19–P21 and only slow resolution thereafter. Complete NV resolution in PWG pups is only reached by P35. Concordant with the findings for NV, the time course and severity of VO also differs significantly between groups (Figure 1D). EWG mice show the quickest VO repair followed closely by MWG mice (13.8 ± 1.2 versus 16.9 ± 0.8% VO at P17; P > 0.05). PWG mice, in contrast, exhibit a markedly delayed VO repair with 25.2 ± 0.8%VO remaining at P17 (P < 0.0001) and 5% of the retina still being avascular by P35. To investigate whether postnatal weight gain is causally linked to the observed differences in OIR patterns, we separated each of three C57BL/6 litters into two groups at P1. One-half of each litter (three pups) remained with their nursing mother. The other half of each litter was transferred to a new cage with two surrogate dams. Importantly, at P1 when the litters were separated, weights are evenly distributed across groups (Figure 1B). This experimental setup allowed us to investigate i) whether differences in postnatal nutritional supply determine in which weight group the litter-matched pups develop and ii) whether pups from the same litter develop different degrees of retinopathy based on their nutritional supply. Our results demonstrate that in all three litters, the pups with an additional surrogate dam develop into EWG pups (8.85 ± 0.5 g at P17), while their littermates without surrogate follow the MWG growth curve (6.67 ± 0.5 g at P17; Figure 1E). OIR pups with an extra surrogate dam exhibit better weight gain and lower NV at P17 compared with pups reared by only their mother (3.7 ± 0.8 versus 8.0 ± 0.4%NV; P < 0.01; Figure 1F). VO at P17 does not differ with the addition of a surrogate (16.0 ± 3.0 versus 19.0 ± 1.6%VO; P > 0.05; Figure 1G). These results parallel the values obtained for EWG and MWG mice in the larger cohort (Figure 1, C and D) and thus provide evidence that alteration of nutritional supply in littermate-controlled mice (presenting identical genetic backgrounds) alters postnatal weight gain and the severity of retinopathy. PWG pups do not arise in these littermate-controlled experiments because due to the litter split at P1, the two groups contain only three to four pups each, and even with only one dam, adequate nutritional supply for three to four pups is provided. After establishing a correlation between nutritional supply, postnatal weight gain, and pathological retinal angiogenesis, we aimed to investigate potential differences in retinal VEGF expression between groups. VEGF was significantly up-regulated during the hypoxic phase of OIR in all three groups (P15–P21; Figure 2A–C). Notably, in each weight group, the time course of VEGF expression (bars) parallels the time course of NV (lines). EWG mice show the least VEGF up-regulation, peaking at P17 together with the peak of NV formation. MWG mice display a similar time course of VEGF induction, however, with significantly higher VEGF up-regulation at P17 that matches the more pronounced NV spike at P17. PWG mice, in contrast, exhibit a prolonged VEGF up-regulation with a broad peak from P19–P21 that parallels the protracted NV formation in these pups. Lectin-stained representative retinal flat-mounts illustrate the described differences in NV and VO time courses (Figure 2, right panel). Protein measurements for VEGF show a tight correlation with the mRNA data and confirm the limited VEGF up-regulation in EWG pups at P17 compared with PWG or MWG pups (Supplemental Figure 1A, see http://ajp.amjpathol.org). These results establish a correlation between postnatal weight gain, retinal VEGF overexpression, and the course of proliferative retinopathy. In addition to analyzing local VEGF up-regulation in the retina of OIR mice, we aimed to indentify serum markers that were differentially regulated between the three postnatal weight gain groups. Because fasting measurements are not feasible in nursing pups we tested glucose, IGF-1, and insulin under non-fasting conditions (at the same hour of the day to control for circadian fluctuations). Both non-fasting glucose and insulin levels have been shown to correlate with food intake.13Emberson JR Whincup PH Walker M Thomas M Alberti KG Biochemical measures in a population-based study: effect of fasting duration and time of day.Ann Clin Biochem. 2002; 39: 493-501Crossref PubMed Scopus (80) Google Scholar In our study, non-fasting glucose and insulin were highest in EWG pups and lowest in PWG pups at P17, indicating enhanced nutrient intake in EWG pups and deficiencies in PWG pups (Figure 3, A and B). This notion is supported by increased ghrelin levels in PWG pups at P17 (Figure 3C). Ghrelin is a peptide hormone that is released from gastric endocrine cells during fasting.21Toshinai K Mondal MS Nakazato M Date Y Murakami N Kojima M Kangawa K Matsukura S Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration.Biochem Biophys Res Commun. 2001; 281: 1220-1225Crossref PubMed Scopus (556) Google Scholar Increased serum ghrelin levels in PWG pups therefore indicate a fasting state in PWG pups compared with EWG or MWG pups at P17. Importantly, increased ghrelin, reduced blood glucose and low serum insulin levels at P17 coincide with the weight loss phase in PWG pups (P12–P17; Figure 1B). In line with data from clinical studies showing a correlation between low IGF-1 and poor postnatal weight gain,6Lofqvist C Andersson E Sigurdsson J Engstrom E Hard AL Niklasson A Smith LE Hellstrom A Longitudinal postnatal weight and insulin-like growth factor I measurements in the prediction of retinopathy of prematurity.Arch Ophthalmol. 2006; 124: 1711-1718Crossref PubMed Scopus (218) Google Scholar, 7Lofqvist C Hansen-Pupp I Andersson E Holm K Smith LE Ley D Hellstrom A Validation of a new retinopathy of prematurity screening method monitoring longitudinal postnatal weight and insulinlike growth factor I.Arch Ophthalmol. 2009; 127: 622-627Crossref PubMed Scopus (136) Google Scholar our data also demonstrate significantly lower IGF-1 levels in PWG pups compared with EWG or MWG pups at P17 (Figure 3D). At P19, however, when NV formation starts to peak in PWG pups, IGF-1 levels have risen to normal values (Supplemental Figure 1B, see http://ajp.amjpathol.org). Importantly, equal levels of nonfasting blood glucose, but increased levels of serum insulin are found in surrogated versus nonsurrogated groups at P17 (Figure 3, E and F). This pattern resembles the difference observed between EWG versus MWG pups in the larger cohort at P17 and is indicative of more frequent feeding and better metabolic supply in surrogated pups. Combined, these results demonstrate that the different weight gain groups have distinct levels of serum markers associated with metabolic supply and energy sensing that can be modified by altering nutritional supply. To evaluate whether the observed perinatal differences in metabolic supply, retinal VEGF expression, and OIR severity translate into persistent phenotypic changes in adult mice, we analyzed retinas from both EWG and PWG mice at P70 (Figure 3, G and H). Although EWG pups represent mice with the most benign course of retinopathy while PWG pups represent mice with significantly prolonged vascular injury, we observed no obvious morphological differences between EWG and PWG mice on H&E-stained retinal cross-sections at P70 (Figure 3G). Similarly, both groups do not differ in retinal vascularization at P70, indicating that repair of the OIR-induced vascular damage as assessed in retinal cross section is complete in both groups by this age (Figure 3H). Notably, adult EWG and PWG mice do display a significant body weight difference at P70 (23.05 ± 0.75" @default.
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• W1991970086 title "Postnatal Weight Gain Modifies Severity and Functional Outcome of Oxygen-Induced Proliferative Retinopathy" @default.
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• W1991970086 doi "https://doi.org/10.2353/ajpath.2010.100526" @default.
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