Journal Article


Thyroid deficiency before birth alters the adipose transcriptome to promote overgrowth of white adipose tissue and impair thermogenic capacity

Abstract

Background. 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 in utero 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. Methods. 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 (white) and multilocular (brown) adipocytes, and unilocular 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. Results. Hypothyroidism in utero resulted in elevated plasma insulin and leptin concentrations and overgrowth of PAT in the fetus, specifically due to hyperplasia and hypertrophy of unilocular adipocytes with no change in multilocular adipocyte mass. RNA-sequencing and genomic analyses showed that thyroid deficiency affected 34% of the genes identified in fetal adipose tissue. Enriched KEGG and gene ontology pathways were associated with adipogenic, metabolic and thermoregulatory processes, insulin resistance, and a range of endocrine and adipocytokine signalling pathways. Adipose protein levels of signalling molecules, including phosphorylated S6-kinase (pS6K), glucose transporter isoform 4 (GLUT4) and peroxisome proliferator-activated receptor ╬│ (PPAR╬│), 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 multilocular adipocyte mass. Conclusions. Growth and development of adipose tissue before birth is sensitive to thyroid hormone status in utero. 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.

Attached files

Authors

Harris, Shelley E.
De Blasio, Miles J.
Zhao Xiaohui
Ma, Marcella
Davies, Katie
Wooding, Peter
Hamilton, Russell S.
Blache, Dominique
Meredith, David
Murray, Andrew J.
Fowden, Abigail L.
Forhead, Alison J.

Oxford Brookes departments

Department of Biological and Medical Sciences

Dates

Year of publication: 2020
Date of RADAR deposit: 2020-02-20



All rights reserved. Final publication is available from Mary Ann Liebert, Inc., publishers https://doi.org/10.1089/thy.2019.0749.


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