Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

Abstract

Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood.

Investigating the Effect of Experimental Hypothyroidism on Insulin/Thyroid Hormones and Hepatic Steatosis

“…Our histological data (Figures 1 and 2) are in agreement with previous reports (23) suggesting that PTU-induced hypothyroidism leads to fat deposition and mild steatosis in the liver. There are miscellaneous reports in conformity with our findings, which show lipid depositions in drug-induced hypothyroid models (22,23), whereas there are also some in contrast (24,25). Our histological studies indicated the accumulation of glycogen depositions in the liver of the hypothyroid group as suggested by others (26).…”

Congenital Hypothyroidism is Associated With Impairment of the Leptin Signaling Pathway in the Hypothalamus in Male Wistar Animals in Adult Life

“…Corroborating these findings our data of low FT3 and FT4 serum levels and normal TSH in both G and GL groups in adulthood suggest that hypothyroidism induced in early life altered the thyroid gland function leading to a condition of hypothyroxinemia [30]. Similar models of hypothyroidism induced in early life [23,24,31,32] did not show the same results. It is possible that the window of treatment and/or the MMI dose used to induce hypothyroidism could have influenced the different results seen among the studies.…”

Neonatal Persistent Exposure to 6‐Propyl‐2‐thiouracil, a Thyroid‐Disrupting Chemical, Differentially Modulates Expression of Hepatic Catalase and C/EBP‐β in Adult Rats

“…It is reported that the formation of a mature hypothalamus–pituitary–thyroid axis is completed in rats by the third week of life . Several biochemical functions of rat liver related to metabolism of carbohydrates and lipids continue to develop after birth and achieved their full capacity approximately by the first month of the life and considerably influenced by thyroid hormones (THs) .…”