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A delicate balance on thyroid hormones controls metabolic health and longevity in mice

ABSTRACT: An inverse correlation between circulating thyroid hormone levels and longevity has been reported in several species and reduced thyroid hormone levels have been proposed as a biomarker for healthy aging and metabolic fitness in humans. However, hypothyroidism is a serious medical condition associated with reduced health and life expectancy. In this report, we show that severe and even subtle modulations on thyroid hormone levels leading to different forms of hyperthyroidism and hypothyroidism produce an overall unhealthy status and reduced lifespan in mice. A mild reduction in circulating T4 levels (~10%) resulted in hepatic mitochondrial dysfunction, increased ROS production and oxidative damage accumulation. These actions may contribute to the development of metabolic disorders, increased prevalence of hepatocellular carcinomas and early mortality in mice. Our findings raise concerns regarding the development of interventions aiming to modulate thyroid hormones to promote healthy aging or lifespan extension in mammals.

ORGANISM(S): Mus musculus

PROVIDER: GSE123288 | GEO | 2020/04/13

REPOSITORIES: GEO

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Project description:Transcriptional profiling of rat liver comparing male rats with congenital hypothyrodism (CH) vs intact at adulhood. Here we studied how CH influences liver gene expression program in adulthood. 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 liver gene expression program in adulthood. Pregnant rats were given anti-thyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as a reduction in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, feed efficiency increased in CH and this was accompanied by significant catch-up growth. On PND80, significant reduction in body mass, tail length, and circulating IGF-I remained in CH rats. On the other hand, mRNA levels of known GH targeted genes were significantly up-regulated. Serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in expression for hepatic genes involved in lipid metabolism with an increased transcription of PPAR and reduced expression of genes involved in fatty acids and cholesterol uptake, cellular sterol efflux, triglycerides assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to hypothyroidism onset in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters, and to T3 replacement with enhanced activation of lipogenic transcriptional program. In summary, we provided in vivo evidence that neonatal hypothyroidism causes long-lasting effects on hepatic transcriptional program and tissue sensitivity to hormone treatment. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood. Two conditions CH vs INTACT male rats. Biological replicates: Four independent hybridizations: 4 controls (age-matched intact rats) vs 4 CH (male rats with congenital hypothyroidism) on postnatal day 80 for a total of four arrays. One replicate per array.

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A delicate balance on thyroid hormones controls metabolic health and longevity in mice

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