Childhood obesity in the USA has increased ~7-fold over the past three decade. In a variety of species substantial evidence supports the concept that development under conditions of an `adverse intrauterine environment' permanently programs the fetus leading to obesity, metabolic disorders and cardiovascular disease as adults. Hypoxia is a major threat to the developing fetus, occurring in situations such as preeclampsia, preterm labor, maternal obesity, placental insufficiency, smoking and high altitude. We have a developed a model of long-term hypoxia (LTH) in sheep where the fetus is exposed to high altitude (3,280m) induced moderate hypoxia from ~40 days of gestation (dG) onward (term is ~146dG). We have reported a significant impact of LTH on perirenal fat (PRF) in the fetus with upregulation of expression of the thermogenic mediator uncoupling protein 1 (UCP1) and genes that support UCP1 expression similar to `brown' adipose tissue (BAT). Unlike true BAT however, PRF rapidly loses the BAT phenotype post- birth, while retaining/expanding the white adipose tissue (WAT) phenotype. Recently, beige/BRITE1 (`brown- in-white') adipocytes have been characterized that reside in WAT. This process, termed `beiging', and has been shown to be protective against obesity in rodents by virtue of lipid mobilization. However, this process has not been studied in animals such as sheep or humans where adipose expands and differentiates in utero. We found that by post-natal day 14 (PN14) LTH lambs exhibit a significant decrease in the BAT/beige molecular program (UCP1, DIO2, PRDM16, PGC1a) compared to control lambs, while retaining and/or amplifying genes of the WAT phenotype (e.g. RIP140, a key co-repressor of BAT genes) indicative of a decreased capacity for beiging and/or a potential loss of BRITE adipocytes, placing these animals at risk for later obesity. The global hypothesis is that gestational LTH reprograms the beiging capacity of PRF, reducing the favorable BRITE adipocyte population.
The Specific Aims will focus on the role of key factors such as sympathetic innervation and fibroblast growth factor 21 (FGF21) on the BAT/beige molecular program in adipose tissue from near term fetuses and postnatal lambs utilizing both in vitro and in vivo studies. Western analysis, qRT-PCR, in situ hybridization and immunocytochemical techniques will be utilized. The results obtained from this Project will dramatically further our understanding of both the mechanism(s) by which moderate gestational hypoxia programs the developing adipose tissue as well as identifying potential means to ameliorate or reverse the impact of LTH on adipose tissue function in these offspring. If successful, our findings could provide both a means for identifying children at high risk for obesity as well as means for intervention of childhood obesity.
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