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 (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. 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 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 c (PPARc), 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. 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.

Development of cerebral mitochondrial respiratory function is impaired by thyroid hormone deficiency before birth in a region‐specific manner

“…Plasma T 4 concentrations were significantly less in TX than control fetuses throughout, and did not differ with age in either group (Table 1). Consistent with previous findings, 14,24 thyroidectomy attenuated the normal prepartum rise in cortisol concentrations with significantly lower values in TX than control fetuses by 142 dGA (Table 1).…”

“…10,11 More recent studies have also shown that thyroid hormones are involved in the normal perinatal maturation of mitochondrial OXPHOS capacity in metabolic tissues including liver, skeletal muscle, and adipocytes. [12][13][14] However, relatively little is known about the role of thyroid hormones in cerebral mitochondrial development, 15 despite the high energy demands associated with the increased neuronal differentiation and activity during the perinatal period. 16 In adult tissues, thyroid hormones regulate many aspects of mitochondrial function including the abundance of the electron transfer system (ETS) complexes generating the electrochemical proton gradient driving ATP production, the uncoupling proteins (UCPs) dissipating this gradient, and the adenine nucleotide translocases (ANTs) that transports ADP into and ATP out of the mitochondria.…”

“…Hypothyroidism is known to limit this rise in oxygen consumption and impair thermogenesis in newborn lambs 10,11 . More recent studies have also shown that thyroid hormones are involved in the normal perinatal maturation of mitochondrial OXPHOS capacity in metabolic tissues including liver, skeletal muscle, and adipocytes 12‐14 . However, relatively little is known about the role of thyroid hormones in cerebral mitochondrial development, 15 despite the high energy demands associated with the increased neuronal differentiation and activity during the perinatal period 16 …”

Thyroid Hormone Deficiency Suppresses Fetal Pituitary–Adrenal Function Near Term: Implications for the Control of Fetal Maturation and Parturition

“…The effects of thyroid hormone deficiency in utero on the developing HPA axis may be direct and/or secondary to other endocrine changes. Hypothyroidism in the sheep fetus is associated with increased circulating concentrations of insulin and leptin, which originate from changes in the structure and function of the fetal pancreas and adipose tissue, respectively (9,10). In fetal sheep, intravenous infusion of leptin to supraphysiological concentration has been shown to prevent the normal increments in plasma ACTH and cortisol seen towards term (40), and to suppress adrenal responsiveness to ACTH challenge and decrease the adrenal mRNA and protein content of the ACTH receptor, StAR and CYP21 in mildly hypoxic fetuses (41).…”

Is Upregulation of Sarcolipin Beneficial or Detrimental to Muscle Function?

“…We found that gradual cold adaptation of neonatal mice prevents programmed developmental downregulation of SLN expression in adult quadriceps and gastrocnemius, glycolytic muscles ( Pant et al, 2015a ). Neonatal mice have significant amounts of BAT with very high UCP1 expression ( Cannon and Nedergaard, 2004 ; Harris et al, 2020 ; Liu et al, 2020 ) and, therefore, it can be argued that the thermogenic demand of neonatal mice is met by BAT based NST. The finding that UCP1 −/− neonates are able to survive at 22°C (below thermoneutrality of 28°C) and can be gradually cold adapted to 4°C suggests the existence of additional NST components ( Enerback et al, 1997 ).…”