Thyroxine Treatment During the Perinatal Stage Prevents the Alterations in the ObRb-STAT3 Leptin Signaling Pathway Caused by Congenital Hypothyroidism

Abstract

Thyroid hormone deficiency during crucial stages of development causes congenital hypothyroidism. This syndrome alters hypothalamic pathways involved in long-term bodyweight regulation as ObRb-STAT3 leptin signaling pathway, which is associated with metabolic syndrome. This study aimed to determine if thyroxine treatment during pregnancy and lactation in hypothyroid mothers avoids, in the congenital hypothyroid offspring, the alterations in metabolic programming related to metabolic syndrome and the ObRb-STAT3 leptin signaling pathway in hypothalamus. Twenty-four virgin female Wistar rats were divided into euthyroid, hypothyroid, and hypothyroid with thyroxine treatment (20 μg/kg/day T4 since pregnancy until lactation). The bodyweight and energy intake, insulin resistance, glucose tolerance, metabolic and hormonal parameters were determined in offspring at 28 weeks after birth. Then, the rats were euthanized to obtain adipose tissue reserves and hypothalamus to measure the expression of ObRb, STAT3, pSTAT3, and SOCS3. Congenital hypothyroidism presented metabolic syndrome such as insulin resistance, glucose tolerance, dyslipidemias, an increase in cardiovascular risk (Castelli I males:166.67%, females: 173.56%; Castelli II males: 375.51%, females: 546.67%), and hypothalamic leptin resistance (SOCS3, Males: 10.96%, females: 25.85%). Meanwhile, the thyroxine treatment in the mothers during pregnancy and lactation prevents the metabolic disturbance. In conclusion, thyroxine treatment during the critical perinatal stage for metabolic programming prevents congenital hypothyroidism-caused metabolic syndrome and hypothalamic leptin resistance.

The joint effect of congenital hypothyroidism and hypercaloric diet consumption as triggers of type 2 diabetes mellitus

“…Also, in previous studies, we have reported the status of thyroid function at various stages of development using the same experimental model as the one used for the present work. The results obtained show that thyroid function in congenital hypothyroid pups remains low throughout development ( 12 , 13 , 14 ).…”

“…Rats fed a hypercaloric diet for 40 weeks had the highest hyperleptinemia levels with physiological leptin resistance. But usually, the leptin resistance can only be demonstrated by a molecular evaluation of hypothalamic SOCS3 overexpression because energy intake does not change ( 14 , 15 ). The results obtained show that a mild disturbance in the lipid contents of the diet produces metabolic damage, causing dyslipidemia, hyperleptinemia, and alterations in cardiovascular risk markers as Castelli index I and II.…”

“…Hypothyroidism was induced surgically by a thyroidectomy with parathyroid reimplantation in the hypothyroid group as previously described ( 12 , 13 , 14 , 17 ). Seven days post-surgery, three females were placed with one male for mating.…”

“…In humans, some meta-analyses reveal an association between hypothyroidism, obesity, and dyslipidemia; however, it is necessary for more studies because multifactorial situations distort the association between the variables (8,9,10,11). On the other hand, previously in animal models, we reported the increased risk to develop T2D in congenital hypothyroid rats because they develop metabolic syndrome even when they are fed with a standard-balanced diet (12,13,14). The mentioned studies reveal that congenital hypothyroidism modifies the metabolic programming promoting dyslipidemia and hyperleptinemia with a change in the thyroid gland's function (12,15).…”

Paternal developmental thyrotoxicosis disrupts neonatal leptin leading to increased adiposity and altered physiology of the melanocortin system

“…For example, neonatal excess in T3 levels, as that observed in Dio3-/- mice and neo-T4 rats, also influences the programming of HPT axis and leptin-melanocortin system ( 47 , 78 , 79 ). Low neonatal levels of thyroid hormone can also determine hypothalamic leptin signaling in adult life ( 80 ). However, we observed no alterations in that regard.…”