Ovine prenatal growth-restriction and sex influence fetal adipose tissue phenotype and impact postnatal lipid metabolism and adiposity in vivo from birth until adulthood

Adipose tissue development begins in utero and is a key target of developmental programming. Here the influence of nutritionally-mediated prenatal growth-restriction on perirenal adipose tissue (PAT) gene expression and adipocyte phenotype in late fetal life was investigated in both sexes in an ovine model. Likewise circulating leptin concentrations and non-esterified fatty acid (NEFA) and glycerol responses to glucose challenge were determined in relation to offspring adiposity at key stages from birth to mid-adult life. In both studies’ singleton-bearing adolescent sheep were fed control or high nutrient intakes to induce normal or growth-restricted pregnancies, respectively. Fetal growth-restriction at day 130 of gestation (32% lighter) was characterised by greater body-weight-specific PAT mass and higher PAT expression of peroxisome proliferator-activated receptor gamma (PPARɤ), glycerol-3-phosphate dehydrogenase, hormone sensitive lipase (HSL), insulin-like growth factor 1 receptor, and uncoupling protein 1. Independent of prenatal growth, females had a greater body-weight-specific PAT mass, more multilocular adipocytes, higher leptin and lower insulin-like growth factor 1 mRNA than males. Growth-restricted offspring of both sexes (42% lighter at birth) were characterised by higher plasma NEFA concentrations across the life-course (post-fasting and after glucose challenge at 7, 32, 60, 85 and 106 weeks of age) consistent with reduced adipose tissue insulin sensitivity. Circulating plasma leptin correlated with body fat percentage (females>males) and restricted compared with normal females had more body fat and increased abundance of PPARɤ, HSL, leptin and adiponectin mRNA in PAT at necropsy (109 weeks). Therefore, prenatal nutrient supply and sex both influence adipose tissue development with consequences for lipid metabolism and body composition persisting throughout the life-course.

脂肪组织的发育始于宫内阶段，是发育程序化的关键调控靶点。本研究以绵羊为模型，探究了营养介导的产前生长受限对妊娠晚期胎儿肾周脂肪组织（perirenal adipose tissue, PAT）基因表达及脂肪细胞表型的影响，实验涵盖雌雄两性个体。此外，本研究还测定了循环中瘦素（leptin）浓度，以及葡萄糖负荷下的非酯化脂肪酸（non-esterified fatty acid, NEFA）与甘油应答水平，并分析其与子代从出生至成年中期关键阶段体脂状态的关联。两项实验均选用单胎妊娠的青年绵羊，分别饲喂正常营养摄入量与高营养摄入量，以构建正常妊娠与生长受限妊娠模型。妊娠第130天时的胎儿生长受限（胎儿体重较正常对照组低32%）表现为：单位体重对应的PAT质量更高，且PAT组织中过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor gamma, PPARɤ）、甘油-3-磷酸脱氢酶、激素敏感性脂肪酶（hormone sensitive lipase, HSL）、胰岛素样生长因子1受体以及解偶联蛋白1的表达水平更高。无论产前生长状态如何，雌性个体的单位体重PAT质量均高于雄性，且拥有更多的多室脂肪细胞，其瘦素表达水平更高，而胰岛素样生长因子1 mRNA表达水平更低。两性中生长受限的子代（出生时体重较正常对照组低42%）在整个生命周期（空腹后以及7、32、60、85和106周龄时进行葡萄糖负荷后）的血浆NEFA浓度均更高，这与脂肪组织胰岛素敏感性降低的表型一致。循环血浆瘦素水平与体脂百分比呈正相关（雌性>雄性）；与正常妊娠组雌性子代相比，生长受限组雌性子代在109周龄尸检时拥有更多体脂，且其PAT组织中PPARɤ、HSL、瘦素及脂联素（adiponectin）的mRNA丰度均更高。综上，产前营养供给与性别均会影响脂肪组织发育，其对脂质代谢与体成分的影响将贯穿整个生命周期。