Thyroid Function and Body Weight Programming by Neonatal Hyperthyroidism in Rats - The Role of Leptin and Deiodinase Activities

Abstract

Several authors have shown that secondary hypothyroidism was programed by neonatal thyroxine (T4) treatment. However, the associated changes of body weight (BW) were less studied, especially those related to the body fat proportion. Here, we have evaluated the effect of neonatal thyroxine treatment on BW, fat proportion, serum leptin, and thyroid function of 60-day-old rats. Wistar rats were treated with thyroxine (50 microg/100 g BW, ip) (T) or saline (S), during the first 10 days of life. BW, nose-rump length (NRL), and food consumption were monitored for 60 days, when the animals were sacrificed. Thyroid function was evaluated by thyroid radioiodine uptake (RAIU), serum T3, T4, TSH, and liver mitochondrial alpha-glycerophosphate dehydrogenase (mGPD) and type 1 and 2 deiodinases (D1 and D2) activities, which are thyroid hormone-dependent enzymes. T animals showed lower food intake, BW and NRL, but higher total fat mass (+33%) and serum leptin (+46%). They also showed lower serum T3 (-23%), T4 (-32%), TSH (-36%), RAIU (-29%) and mGPD activity (-22%). Hypothalamic and pituitary D2 activities were higher (+24% and 1.4 fold, respectively), while brown adipose tissue (BAT) D2 and skeletal muscle D1 activities were lower (-30% and -62%, respectively). Thus, neonatal hyperthyroidism programs for a higher fat proportion and hyperleptinemia, which can explain the lower food intake. The TH-dependent enzymes activities changed accordingly, except for the decrease in BAT D2, which may be due the role played by the hyperleptinemia. Finally, the decrease in peripheral deiodination may contribute to a lower me-tabolic rate that may increase the adiposity.

Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity

“…This idea is supported by previous observations in mice that the first week after birth constitutes a "sensitive" period during which transient activation of thyroid hormone signaling can have permanent life-long effects, such as decreased hepatic EGF receptor number and body growth (25), increased adiposity (26), and precocious puberty (27). These effects can be seen after a short course of thyroid hormone administration, as well as in animals with targeted disruption of the type 3 deiodinase, which inactivates both T4 and T3 (27).…”

Pro-TRH and pro-CRF expression in paraventricular nucleus of small litter-reared fasted adult rats

“…This animal model may be useful for understanding the refractoriness of adults with infant obesity or the offspring of diabetic mothers (Dussault et al 1982, Walker & Courtin 1985, Pracyk et al 1992, Cetin et al 2000, Tapanainen et al 2001, Wilcoxon & Redei 2004, Moura et al 2008 to reduce weight in response to diet therapy and their propensity to develop obesity and its co-morbidities.…”

Postnatal overnutrition programs the thyroid hormone metabolism and function in adulthood

“…In summary, it is known that epigenetic mechanisms, such as DNA methylation, histone acetylation and deacetylation, or microRNA, induced by pre-and postnatal factors such as nutrition and hormones, may lead to a higher risk of metabolic diseases in the adult life of the offspring (de Moura et al 2008). This explanation may help us understand the permanent changes of TRH, TSH, deiodinases, UCP-1 and TRb1 that are caused by EO.…”

“…Epidemiological, clinical and experimental studies have shown that the nutritional, hormonal and environmental factors observed in the early stages of development have long-term effects on hormonal and metabolic homeostasis. This association can be characterized as a metabolic programming phenomenon, which is defined as an association between physical and chemical stimuli in early life and future functional status (de Moura et al 2008).…”