Maintenance of the thyroid axis during diet-induced obesity in rodents is controlled at the central level

Abstract

The hypothalamic-pituitary-thyroid (HPT) axis is a major contributor in maintaining energy expenditure and body weight, and the adipocyte hormone leptin regulates this axis by increasing TRH levels in the fed state. Leptin stimulates TRH directly in the hypothalamic paraventricular nucleus (PVN; direct pathway) and indirectly by regulating proopiomelnocortin neurons in the hypothalamic arcuate nucleus (ARC; indirect pathway). Whereas the indirect pathway is fully functional in lean animals, it is inactive during diet-induced obesity (DIO) because of the establishment of leptin resistance. Despite this, the HPT axis activity in obese humans and rodents remains within the normal levels or slightly higher. Therefore, in this study, we aimed to determine the mechanism(s) by which the HPT axis is still active despite leptin resistance. With a combination of using the Sprague-Dawley rat physiological model and the Zuker rat that bears a mutation in the leptin receptor, we were able to demonstrate that under DIO conditions the HPT axis is regulated at the central level, but only through the direct pathway of leptin action on TRH neurons. Deiodinase enzymes, which are present in many tissues and responsible for converting thyroid hormones, were not statistically different between lean and DIO animals. These data suggest that the increase in T(4/3) seen in obese animals is due mostly to central leptin action. We also found that T(3) feedback inhibition on the prepro-TRH gene is controlled partially by leptin-induced pSTAT3 signaling via the TRH promoter. This interactive relationship between T(3) and pSTAT3 signaling appears essential to maintain the HPT axis at normal levels in conditions such as obesity.

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

“…T 4 serum content is slightly decreased in the early-overfed group according to Plagemann et al (1999) and we found that proTRH expression in the mPVN subcompartment was also lower than that in controls. Since early-overfed adult rats were overweight, the HPT axis must be activated, as is observed in obese humans and in some obesity models in rodents (Reinehr & Andler 2002, Perello et al 2010. However, the early-overfed group exhibited an altered flexibility of the HPT axis to increased adiposity, which might induce, in the long term, deceleration of the metabolic rate, and favor the development of obesity and its complications.…”

“…This fasting-induced shift in circulating hormone concentration activates type 2 deiodinase (D2) enzymatic activity in the median eminence (Coppola et al 2005a), which in turn increases local T 3 content in the hypothalamus, inhibiting proTRH expression. In contrast, hyperphagia and being overweight lead to high leptin and T 3 serum levels in humans (Reinehr 2011) and rodents (Perello et al 2010), as well as increased PVN proTRH expression in adult offspring of dams fed a high-fat diet (Franco et al 2012). These manifestations act as counterregulatory mechanisms in response to high body adiposity.…”

60 YEARS OF NEUROENDOCRINOLOGY: TRH, the first hypophysiotropic releasing hormone isolated: control of the pituitary–thyroid axis

“…Diet-induced obesity (DIO) enhances HPT axis activity in male rats, as demonstrated by increased Trh mRNA levels in the hypothalamus/PVN and serum TSH concentration. This increase in HPT axis activity may be due to enhanced circulating leptin levels acting directly on PVN-TRH neurons, independently from POMC neurons, thus bypassing the drop of leptin sensitivity which occurs in the ARC during DIO, or through other circuits that maintain leptin sensitivity (Araujo et al 2010, Perello et al 2010. Likewise, mice fed a high fat diet for 7-20 weeks have an activated HPT axis, with higher hypothalamic Trh mRNA levels, and serum TSH concentration than mice on a control diet.…”

Long-term High-Soybean Oil Feeding Alters Regulation of Body Temperature in Rats

“…In contrast, increased UCP mRNA/protein and increased inflammatory adipokine concentrations have also been observed in the hypothalamus/plasma in response to high-fat dietary intervention. 18,20,34,35) In studies when BT was measured after high-fat dietary intervention, either an increase or no change in BT have both been observed. 16,[19][20][21]36,37) Our results show that HSD and HLD produced hypothermia, whereas HFD did not influence BT.…”

“…[15][16][17][18] However, when BT is actually measured during intervention of high-fat diet, various results on BT, hyperthermia, hypothermia or no changes, are reported. 5,16,[19][20][21] As one of the reasons of the inconsistent results, the differences among experimental conditions, such as kinds of high-fat diets and feeding period, are raised. In this study, we used three kinds of high-fat diet, and investigated effects of dietary fat on BT regulation.…”