Goyal Michell, Luna Ramirez Rosa I, Limesand Sean W, Goyal Ravi
Departmet of Physiology, University of Arizona, Tucson, Arizona, USA.
School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, Arizona, USA.
Physiol Rep. 2024 Dec;12(23):e70143. doi: 10.14814/phy2.70143.
Fetal growth restriction (FGR) is a risk factor for obesity in adult life. Importantly, growth-restricted females are more prone to obesity than males. The mechanisms involved in this sexually dimorphic programming are not known. Previously, we have demonstrated that ambient hyperthermia (40°C) led to placental insufficiency and significant FGR, and the perirenal adipose tissue undergoes sexually dimorphic gene expression. We demonstrated that males undergo significant changes in gene expression with growth restriction. This was not the case in females. We have also demonstrated that the isolated preadipocytes from male FGR (MFGR) have reduced differentiation potential compared to control males & females and female FGR (FFGR). Thus, we hypothesized that growth restriction differentially programs gene expression and genetic pathways in perirenal preadipocytes, which reduces their differentiation potential in male fetuses in a sexually dimorphic manner. We created FGR by exposing pregnant sheep to ambient hyperthermia. After isolating preadipocytes from perirenal adipose tissue, we differentiated them following published protocols. We examined the gene expression before and after differentiation from control male, control female, MFGR, and FFGR female. We also compared our data with other published studies in mouse and human preadipocytes. Our results demonstrate that a set of 21 genes altered with preadipocyte differentiation to mature adipocytes is common in adipose tissue from both sexes, humans, mice, and sheep, at different organismal ages (embryonic, fetal, and adult) and different sites (subcutaneous inguinal, pancreatic, perirenal). We also demonstrate that female FFGR fetuses demonstrate all these 21 genes altered similar to control males and females; however, MFGR fetuses have six genes (Dgat2, Fabp4, Lipe, Lrrfip1, Spred3, and Thrsp) that are not changed with preadipocyte differentiation to mature adipocyte. These genes may be responsible for reduced differentiation potential and obesity in FGR males compared to FGR females. Another important finding of the present study is that Lrrfip1, known to be associated with obesity, was upregulated with FGR and requires further investigation. Overall, our studies provide several target genes that may play a crucial role in reducing the risk of MFGR for obesity.
胎儿生长受限（FGR）是成年后肥胖的一个风险因素。重要的是，生长受限的雌性比雄性更容易肥胖。这种性别差异编程所涉及的机制尚不清楚。此前，我们已经证明环境高温（40°C）会导致胎盘功能不全和显著的FGR，并且肾周脂肪组织会发生性别差异基因表达。我们证明雄性在生长受限情况下基因表达会发生显著变化。而雌性并非如此。我们还证明，与对照雄性和雌性以及雌性FGR（FFGR）相比，来自雄性FGR（MFGR）的分离前脂肪细胞分化潜能降低。因此，我们假设生长受限以性别差异的方式对肾周前脂肪细胞中的基因表达和遗传途径进行编程，从而降低雄性胎儿中前脂肪细胞的分化潜能。我们通过将怀孕的绵羊暴露于环境高温来制造FGR。从肾周脂肪组织中分离出前脂肪细胞后，我们按照已发表的方案对它们进行分化。我们检查了对照雄性、对照雌性、MFGR和FFGR雌性在分化前后的基因表达。我们还将我们的数据与其他关于小鼠和人类前脂肪细胞的已发表研究进行了比较。我们的结果表明，一组随着前脂肪细胞分化为成熟脂肪细胞而改变的21个基因在不同生物体年龄（胚胎、胎儿和成年）和不同部位（皮下腹股沟、胰腺、肾周）的两性、人类、小鼠和绵羊的脂肪组织中是常见的。我们还证明，雌性FFGR胎儿表现出这21个基因的所有改变，与对照雄性和雌性相似；然而，MFGR胎儿有6个基因（Dgat2、Fabp4、Lipe、Lrrfip1、Spred3和Thrsp）在前脂肪细胞分化为成熟脂肪细胞时没有变化。与FGR雌性相比，这些基因可能是导致FGR雄性分化潜能降低和肥胖的原因。本研究的另一个重要发现是，已知与肥胖相关的Lrrfip1在FGR时上调，需要进一步研究。总体而言，我们的研究提供了几个可能在降低MFGR肥胖风险中起关键作用的靶基因。
