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Intravitreally Injected Anti-VEGF Antibody Reduces Brown Fat in Neonatal Mice.

Jo DH, Park SW, Cho CS, Powner MB, Kim JH, Fruttiger M, Kim JH - PLoS ONE (2015)

Bottom Line: Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat.With increasing age and body weight, brown fat restored its morphology and vascularity.We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

View Article: PubMed Central - PubMed

Affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.

ABSTRACT
Anti-vascular endothelial growth factor (VEGF) agents are the mainstay treatment for various angiogenesis-related retinal diseases. Currently, bevacizumab, a recombinant humanized anti-VEGF antibody, is trailed in retinopathy of prematurity, a vasoproliferative retinal disorder in premature infants. However, the risks of systemic complications after intravitreal injection of anti-VEGF antibody in infants are not well understood. In this study, we show that intravitreally injected anti-VEGF antibody is transported into the systemic circulation into the periphery where it reduces brown fat in neonatal C57BL/6 mice. A considerable amount of anti-VEGF antibody was detected in serum after intravitreal injection. Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat. With increasing age and body weight, brown fat restored its morphology and vascularity. Our results show that there is a transient, but significant impact of intravitreally administered anti-VEGF antibody on brown adipose tissue in neonatal mice. We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

No MeSH data available.


Related in: MedlinePlus

Long-term effects of intravitreally injected anti-VEGF antibody on BAT.(A) Quantitative analyses of the number of large lipid droplets (> 50 μm2) per field at x400 magnification (n = 3–6). The effects of anti-VEGF antibody were quantitatively analyzed by comparison to the group treated with intravitreal PBS injection as 100%. (B) Quantitative analyses of vascularity of interscapular BAT demonstrated by isolectin B4 staining (n = 3–6). The effects of anti-VEGF antibody were quantitatively analyzed by comparison to the group treated with intravitreal PBS injection as 100%. (C) The changes in body weight from P14 to P56. Anti-VEGF, anti-VEGF antibody. NS, not significant (two-tailed, unpaired T-test).
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pone.0134308.g003: Long-term effects of intravitreally injected anti-VEGF antibody on BAT.(A) Quantitative analyses of the number of large lipid droplets (> 50 μm2) per field at x400 magnification (n = 3–6). The effects of anti-VEGF antibody were quantitatively analyzed by comparison to the group treated with intravitreal PBS injection as 100%. (B) Quantitative analyses of vascularity of interscapular BAT demonstrated by isolectin B4 staining (n = 3–6). The effects of anti-VEGF antibody were quantitatively analyzed by comparison to the group treated with intravitreal PBS injection as 100%. (C) The changes in body weight from P14 to P56. Anti-VEGF, anti-VEGF antibody. NS, not significant (two-tailed, unpaired T-test).

Mentions: To investigate long-term effects of a single intravitreal injection of anti-VEGF antibody on BAT, we examined the morphology and vascularity of BAT at P42 and P56, 4 and 6 weeks after intravitreal injection, respectively. BAT recovered its normal morphology without the distinct large lipid droplets seen at the earlier time points (Fig 3A and S3A Fig). Furthermore, the BAT vascular network also appeared to be comparable to normal controls treated with PBS (Fig 3B). Also, the expression of mitochondria-related genes in BAT of mice treated with anti-VEGF antibody was also comparable to that of mice treated only with PBS at this time point (S3B Fig). These results are consistent with a previous study which demonstrated that the introduction of transgenic VEGF-A could rescue BAT whitening in mice with targeted deletion of Vegfa in adipose tissue [15]. Likewise, with decreasing concentrations of serum anti-VEGF antibody (Fig 1C), the effects by neutralization of VEGF in BAT were also diminished.


Intravitreally Injected Anti-VEGF Antibody Reduces Brown Fat in Neonatal Mice.

Jo DH, Park SW, Cho CS, Powner MB, Kim JH, Fruttiger M, Kim JH - PLoS ONE (2015)

Long-term effects of intravitreally injected anti-VEGF antibody on BAT.(A) Quantitative analyses of the number of large lipid droplets (> 50 μm2) per field at x400 magnification (n = 3–6). The effects of anti-VEGF antibody were quantitatively analyzed by comparison to the group treated with intravitreal PBS injection as 100%. (B) Quantitative analyses of vascularity of interscapular BAT demonstrated by isolectin B4 staining (n = 3–6). The effects of anti-VEGF antibody were quantitatively analyzed by comparison to the group treated with intravitreal PBS injection as 100%. (C) The changes in body weight from P14 to P56. Anti-VEGF, anti-VEGF antibody. NS, not significant (two-tailed, unpaired T-test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520452&req=5

pone.0134308.g003: Long-term effects of intravitreally injected anti-VEGF antibody on BAT.(A) Quantitative analyses of the number of large lipid droplets (> 50 μm2) per field at x400 magnification (n = 3–6). The effects of anti-VEGF antibody were quantitatively analyzed by comparison to the group treated with intravitreal PBS injection as 100%. (B) Quantitative analyses of vascularity of interscapular BAT demonstrated by isolectin B4 staining (n = 3–6). The effects of anti-VEGF antibody were quantitatively analyzed by comparison to the group treated with intravitreal PBS injection as 100%. (C) The changes in body weight from P14 to P56. Anti-VEGF, anti-VEGF antibody. NS, not significant (two-tailed, unpaired T-test).
Mentions: To investigate long-term effects of a single intravitreal injection of anti-VEGF antibody on BAT, we examined the morphology and vascularity of BAT at P42 and P56, 4 and 6 weeks after intravitreal injection, respectively. BAT recovered its normal morphology without the distinct large lipid droplets seen at the earlier time points (Fig 3A and S3A Fig). Furthermore, the BAT vascular network also appeared to be comparable to normal controls treated with PBS (Fig 3B). Also, the expression of mitochondria-related genes in BAT of mice treated with anti-VEGF antibody was also comparable to that of mice treated only with PBS at this time point (S3B Fig). These results are consistent with a previous study which demonstrated that the introduction of transgenic VEGF-A could rescue BAT whitening in mice with targeted deletion of Vegfa in adipose tissue [15]. Likewise, with decreasing concentrations of serum anti-VEGF antibody (Fig 1C), the effects by neutralization of VEGF in BAT were also diminished.

Bottom Line: Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat.With increasing age and body weight, brown fat restored its morphology and vascularity.We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

View Article: PubMed Central - PubMed

Affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.

ABSTRACT
Anti-vascular endothelial growth factor (VEGF) agents are the mainstay treatment for various angiogenesis-related retinal diseases. Currently, bevacizumab, a recombinant humanized anti-VEGF antibody, is trailed in retinopathy of prematurity, a vasoproliferative retinal disorder in premature infants. However, the risks of systemic complications after intravitreal injection of anti-VEGF antibody in infants are not well understood. In this study, we show that intravitreally injected anti-VEGF antibody is transported into the systemic circulation into the periphery where it reduces brown fat in neonatal C57BL/6 mice. A considerable amount of anti-VEGF antibody was detected in serum after intravitreal injection. Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat. With increasing age and body weight, brown fat restored its morphology and vascularity. Our results show that there is a transient, but significant impact of intravitreally administered anti-VEGF antibody on brown adipose tissue in neonatal mice. We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

No MeSH data available.


Related in: MedlinePlus