Any intravitreally injected substance must prove efficacy and

Any intravitreally injected substance must prove efficacy and safety. While our study was not designed as a preclinical safety study, we did not find any obvious structural changes after Sema3f treatment in either of the two in vivo models, which is not surprising given that Sema3f is physiologically expressed in the outer retina (Buehler et al., 2013). Our long-term follow-up experiments in Vldlr−/− mice showed even improved retinal integrity compared to control treated eyes, which may be a secondary benefit from reduced number and size of subretinal neovascular lesions.
In summary, these data provide to our knowledge the first proof of concept that Sema3f can be used to modulate pathological subretinal neovascularization. The protective effect of Sema3f was observed in two independent model systems and with two independent modes of application. The fact that Sema3f is physiologically expressed in the retina of both mice and humans (Buehler et al., 2013) renders Sema3f a promising target for treating pathological neovascularization formation in AMD.

Conflicts of Interest

Author Contributions

Acknowledgements

Introduction
With metabolic syndromes such as obesity yielding widespread contemporary concern, the race is on for discovering strategies which can ameliorate conditions detrimental to human health. Nutrigenomics is an emerging field of science aiming to address such conditions by studying the molecular interplay between a diet and the genome. Evidence shows that adipose development at the fetal stage have long term effects in later life. In mice, subcutaneous white fat (WAT) (Wang et al., 2013) and brown fat (BAT) (Billon and Dani, 2012) develop during the fetal stage. Maternal nutritional status during gestation epigenetically alters WAT differentiation (Borengasser et al., 2013). Zfp423, a gene encoding a transcription factor for preadipocyte commitment, is hypomethylated in fetuses born to obese mothers (Yang et al., 2013). Moreover, the population of adipose progenitor dihydrofolate reductase inhibitor (Liang et al., 2016a) and the thermogenic function of BAT (Liang et al., 2016b) of offspring are altered due to maternal intake of high fat diet. Up to now, the relationship between early adipose development and obesity in later life remains poorly understood.
White adipocytes are healthy at normal sizes, but over-expansion of adipocyte sizes lead to hypoxia (Sun et al., 2011), inflammation, and interstitial fibrosis (Sun et al., 2013), which triggers adipose metabolic dysfunction (Sun et al., 2014b). Beige adipocytes, which distribute inside white adipose tissue, burn fatty acids to reduce adipocyte hypotrophy. The vascular system acts as an adipogenic niche by providing PDGFRα+ progenitors, which are able to differentiate into both beige and white adipocytes (Lee et al., 2012). Adipose tissue are highly vascularized (Cao, 2007), and adipogenesis is spatially and temporally associated with angiogenesis during fetal development (Cao, 2007), which provides PDGFRα+ progenitor cells (Crisan et al., 2008; Tran et al., 2012; Vishvanath et al., 2016). Thus, promoting beige adipogenesis of PDGFRα+ progenitors improves the metabolic health of adipose tissue.
Vitamin A and its metabolite, retinoic acid (RA), play key roles in fetal morphogenesis and organ development (Zile, 2001; Duester, 2008), and is a common supplement used during pregnancy. At pharmacological doses, RA increases energy consumption of white adipose tissue (Alvarez et al., 1995; Puigserver et al., 1996; Bonet et al., 2003; Mercader et al., 2006), suggesting that RA might promote beige adipogenesis in mature WAT. Vitamin A or RA supplementation is effective in preventing obesity in adult mice (Berry et al., 2012; Noy, 2013). In humans, overweight and obese individuals showed lower retinoid levels in serum (de Souza Valente da Silva et al., 2007; Pereira et al., 2012) and dietary vitamin A intake is inversely related with adiposity (Zulet et al., 2008). However, the effect of maternal vitamin A intake on beige adipogenesis during fetal development is unclear, which represents a critical knowledge gap because the fetal and neonatal stages are critical for adipogenesis. The long-term impact of maternal retinoid status on adipose metabolic health of offspring remains unclear. We hypothesized that maternal vitamin A supplementation promotes angiogenesis and beige adipogenesis during fetal development, which improve the metabolic health of offspring adipose tissue, protecting offspring from diet-induced obesity and metabolic dysfunction.