Maternal vitamin A supplementation increases blood vessel density and expands adipose progenitor population in progeny.
Maternal vitamin A supplementation enhances brown-like phenotype in adipose tissues.
Maternal vitamin A supplementation protects offspring from diet induced obesity.
Vitamin A and its metabolite, retinoic acid, play key roles in adipogenesis and energy expenditure of adipose tissues. In mice and humans, vitamin A intake is inversely correlated with adiposity. This study has uncovered a role for maternal retinoids in fetal adipose development. Maternal vitamin A supplementation or RA administration increases adipose progenitor population and promotes beige adipogenesis, which protects offspring from diet induced obesity in later life.
Maternal vitamin A intake varies but its impact on offspring metabolic health is unknown. Here we found that maternal vitamin A or retinoic acid (RA) administration expanded PDGFRα+ adipose progenitor population in progeny, accompanied by increased blood vessel density and enhanced brown-like (beige) phenotype in adipose tissue, protecting offspring from obesity. Blockage of retinoic acid signaling by either BMS493 or negative RA receptor (RARαDN) over-expression abolished the increase in blood vessel density, adipose progenitor population, and beige adipogenesis stimulated by RA. Furthermore, RA-induced beige adipogenesis was blocked following vascular endothelial growth factor receptor (VEGFR) 2 knock out in PDGFRα+ cells, suggesting its mediatory role. Our data reveal an intrinsic link between maternal retinoid level and offspring health viapromoting beige adipogenesis. Thus, enhancing maternal retinoids is an amiable therapeutic strategy to prevent obesity in offspring, especially for those born to obese mothers which account for one third of all pregnancies.
In this study, we found that maternal retinoid supplementation profoundly enhances brown/beige adipogenesis during fetal development, which has long-term effect on BAT and beige phenotype in offspring, and protects offspring from diet-induced obesity. This is an exciting discovery considering the easiness of vitamin A supplementation and the wide existence of vitamin A deficiency worldwide (WHO, 2009), particularly in low income countries. Low income correlates with obesity and metabolic diseases (Pan et al., 2013).
We identified that maternal retinoid status affects fetal and offspring brown/beige adipogenesis through promoting angiogenesis. Maternal vitamin A or RA supplementation enhances angiogenesis through upregulating Vegfa and Vegfr2expression, which consequently increased the population of PDGFRα+ adipose progenitor cells in adipose tissue. Our data are consistent the enhanced angiogenesis in both white and brown adipose tissues of mice exposed to cold stimulus, where Vegfr2blockage abolishes the cold-induced angiogenesis and impairs nonshivering thermogenesis capacity ( Xue et al., 2009). Although it remains controversial whether beige adipocytes are generated by de novo adipogenesis or conversion of existing adipocytes ( Rosenwald et al., 2013 ; Wang et al., 2013), progenitor cells on endothelial vessels are capable to differentiate into beige adipocytes ( Tran et al., 2012; Min et al., 2016 ; Vishvanath et al., 2016). Obesity and diabetes impair the angiogenic potential of adipose tissue stem cells ( Rennert et al., 2014 ; Togliatto et al., 2016), and stimulation of angiogenesis via Vegfa over-expression promotes adipose tissue thermogenesis and protects against diet-induced obesity ( Wu et al., 2011 ; Sun et al., 2014a). Thus, enhancing angiogenesis is an effective strategy to promote beige adipogenesis in adipose tissue impaired due to obesity and diabetes.
Besides stimulating angiogenesis, our data also show that maternal vitamin A or RA supplementation up-regulates brown/beige adipogenesis of progenitor cells, which is associated with enhanced expression of Prdm16 and other brown adipocyte genes. Using mice with conditional Vegfr2 knockout specifically in PDGFRα+ progenitor cells, the promotion effect of RA on brown adipogenesis was severely reduced, demonstrating an angiogenesis independent effect of RA on beige adipogenesis. These observations are consistent with previous studies showing that the RA increases oxidation and energy consumption of white adipose tissue in mature animals ( Alvarez et al., 1995; Puigserver et al., 1996; Bonet et al., 2003 ; Mercader et al., 2006). Thus, maternal RA stimulates both angiogenesis and beige adipogenesis during early development, which are mediated by RAR because its functional knockout blocks brown/beige adipogenesis.
Besides beige adipogenesis, increasing the progenitor pool in adipose tissues through angiogenesis has another advantage. It is known that PDGFRα+ progenitor cells are the source of both beige and white adipocytes (Lee et al., 2012; Lee et al., 2013 ; Lee et al., 2015). Thus, enhancing PDGFRα+ progenitor cell pool will not only increase beige but also white adipogenesis, as shown by the increased expression of white preadipose genes in MVA WAT of this study. Adipose tissue is the organ to store fat, and an insufficient number of adipocytes leads to adipocyte hypertrophy, hypoxia and inflammation, a key cause of metabolic dysfunction (Rosen and Spiegelman, 2014). Thus, adipocyte hyperplasia has protective effects on metabolic dysfunction induced by excessive energy intake. Consistently, there is one subgroup of people who are metabolically health despite being obese, while others exhibit severe metabolic syndromes (Denis and Obin, 2013). People who are called “metabolically healthy obese” (MHO) tend to have smaller adipocytes (Kloting et al., 2010) and higher mitochondrial transcription (Naukkarinen et al., 2014). These individuals have reduced visceral adiposity, reduced inflammation, improved glucose and lipid homeostasis when compared to other equally obese unhealthy subjects (Denis and Obin, 2013). Based on our discovery, maternal vitamin A or RA supplementation increases the progenitor pool in offspring, which reduces average adipocyte sizes and increases adipocyte hyperplasia, improving overall metabolic health of offspring.
In conclusion, offspring adipose tissue health is substantially improved due to maternal vitamin A or RA supplementation. Maternal vitamin A promotes vascular system development, which consequently increases the population of PDGFRα+ adipose progenitor cells. In addition, maternal vitamin A supplementation strongly upregulates beige adipogenesis of PDGFRα+ progenitor cells. In combination, maternal vitamin A treated offspring have increased beige adipogenesis and smaller adipocyte sizes, which protect offspring against diet-induced obesity and metabolic dysfunction.