Regulation of thyroid hormone levels by hypothalamic TRH (thyrotropin-releasing hormone) neurons.
Academic Article
Overview
abstract
BACKGROUND: Thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) have been identified as direct regulators of thyroid-stimulating hormone (TSH) and thyroid hormone (TH) levels. They play a significant role in context of negative feedback by TH at the level of TRH gene expression and during fasting when TH levels fall due, in part, to suppression of TRH gene expression. METHODS: To test these functions directly for the first time we used a chemogenetic approach and activated PVN TRH neurons in both fed and fasted mice. Next, to demonstrate the signals that regulate the fasting response in TRH neurons, we activated or inhibited AgRP/NPY neurons in the arcuate nucleus of the hypothalamus (ARC) of fed or fasted mice, respectively. To determine if the same TRH neurons responsive to melanocortin signaling mediate negative feedback by TH, we disrupted the thyroid hormone receptor beta (TRβ) in all MC4R (melanocortin receptor 4) neurons in the PVN. RESULTS: Activation of TRH neurons led to increased TSH and TH levels within 2 hours demonstrating the specific role of PVN TRH neurons in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. Moreover, activation of PVN TRH neurons prevented the fall in TH levels in fasting mice. Stimulation of AgRP/NPY neurons led to a fall in TH levels despite increasing feeding. Inhibition of these same neurons prevented the fall in TH levels during a fast presumably via their ability to directly regulate PVN TRH neurons via, in part, the melanocortin 4 receptor (MC4R). Surprisingly, TH-mediated feedback was not impaired in mice lacking TRβ in MC4R neurons. CONCLUSIONS: TRH neurons are major regulators of the HPT axis and the fasting-induced suppression of TH levels. The latter relies, at least in part, on the activation of AgRP/NPY neurons in the arcuate nucleus. Interestingly, present data does not support an important role for TRβ signaling in regulating MC4R neurons in the PVN. Thus, it remains possible that different subsets of TRH neurons in the PVN mediate responses to energy balance and to thyroid hormone feedback.
