Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom.
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
Thyroid. 2020 Jun;30(6):794-805. doi: 10.1089/thy.2019.0749. Epub 2020 Mar 18.
Development of adipose tissue before birth is essential for energy storage and thermoregulation in the neonate and for cardiometabolic health in later life. Thyroid hormones are important regulators of growth and maturation in fetal tissues. Offspring hypothyroid are poorly adapted to regulate body temperature at birth and are at risk of becoming obese and insulin resistant in childhood. The mechanisms by which thyroid hormones regulate the growth and development of adipose tissue in the fetus, however, are unclear. This study examined the structure, transcriptome, and protein expression of perirenal adipose tissue (PAT) in a fetal sheep model of thyroid hormone deficiency during late gestation. Proportions of unilocular (UL) (white) and multilocular (ML) (brown) adipocytes, and UL adipocyte size, were assessed by histological and stereological techniques. Changes to the adipose transcriptome were investigated by RNA sequencing and bioinformatic analysis, and proteins of interest were quantified by Western blotting. Hypothyroidism resulted in elevated plasma insulin and leptin concentrations and overgrowth of PAT in the fetus, specifically due to hyperplasia and hypertrophy of UL adipocytes with no change in ML adipocyte mass. RNA sequencing and genomic analyses showed that thyroid deficiency affected 34% of the genes identified in fetal adipose tissue. Enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathways were associated with adipogenic, metabolic, and thermoregulatory processes, insulin resistance, and a range of endocrine and adipocytokine signaling pathways. Adipose protein levels of signaling molecules, including phosphorylated S6-kinase (pS6K), glucose transporter isoform 4 (GLUT4), and peroxisome proliferator-activated receptor γ (PPARγ), were increased by fetal hypothyroidism. Fetal thyroid deficiency decreased uncoupling protein 1 (UCP1) protein and mRNA content, and UCP1 thermogenic capacity without any change in ML adipocyte mass. Growth and development of adipose tissue before birth is sensitive to thyroid hormone status . Changes to the adipose transcriptome and phenotype observed in the hypothyroid fetus may have consequences for neonatal survival and the risk of obesity and metabolic dysfunction in later life.
出生前脂肪组织的发育对于新生儿的能量储存和体温调节以及成年后的心脏代谢健康至关重要。甲状腺激素是胎儿组织生长和成熟的重要调节剂。甲状腺功能减退的后代在出生时不能很好地调节体温，并且有在儿童时期肥胖和胰岛素抵抗的风险。然而，甲状腺激素调节胎儿脂肪组织生长和发育的机制尚不清楚。本研究在妊娠晚期甲状腺激素缺乏的胎儿羊模型中检查了肾周脂肪组织（PAT）的结构、转录组和蛋白质表达。通过组织学和体视学技术评估单室（UL）（白色）和多室（ML）（棕色）脂肪细胞的比例以及 UL 脂肪细胞的大小。通过 RNA 测序和生物信息学分析研究了脂肪转录组的变化，并通过 Western 印迹定量了感兴趣的蛋白质。甲状腺功能减退导致胎儿血浆胰岛素和瘦素浓度升高和 PAT 过度生长，这主要是由于 UL 脂肪细胞的增生和肥大，而 ML 脂肪细胞的质量没有变化。RNA 测序和基因组分析表明，甲状腺缺乏影响了胎儿脂肪组织中鉴定出的 34%的基因。富含京都基因与基因组百科全书（KEGG）和基因本体论（GO）途径与脂肪生成、代谢和体温调节过程、胰岛素抵抗以及一系列内分泌和脂肪细胞因子信号通路有关。包括磷酸化 S6-激酶（pS6K）、葡萄糖转运蛋白同工型 4（GLUT4）和过氧化物酶体增殖物激活受体γ（PPARγ）在内的脂肪信号分子的蛋白质水平在胎儿甲状腺功能减退时增加。胎儿甲状腺功能减退降低了解偶联蛋白 1（UCP1）蛋白和 mRNA 含量，以及 UCP1 的产热能力，而 ML 脂肪细胞的质量没有变化。出生前脂肪组织的生长和发育对甲状腺激素状态敏感。在甲状腺功能减退胎儿中观察到的脂肪转录组和表型变化可能对新生儿的生存以及成年后肥胖和代谢功能障碍的风险产生影响。
