Uncovering the Mechanisms by which Oral Thyroid Hormones Influence Energy Balance

Abstract

It has recently been discovered that TH action on body metabolism is not only mediated by direct tissue effects, but also by their action on the CNS, leading to hypothalamic-driven outputs to the peripheral targets, and those effects are integrated in a complex machinery which overall functioning remains to be clarified. As the majority of the central effects have been studied in models of direct hypothalamic TH treatment, one of the most challenging issues is the estimation of the relative contribution of the central vs peripheral component in the more physiologic conditions of peripherally TH release (or administration). In this study we used two different models of peripherally induced hyperthyroidism (i.e. T4 and T3 oral administration) to assess and compare the serum and hypothalamic TH homeostasis and relate them to the observed metabolic effects. TH treatment affected feeding behaviour, overall growth, core body temperature, body composition, BAT morphology and metabolic activity, WAT browning, and liver lipid metabolism, resulting in an increased overall uncoupling capacity and a shift of the lipid metabolism from WAT accumulation to BAT fueling and liver deposition. In the hypothalamus, both treatment protocols induced significant changes in TH concentrations (not always reflecting the correspondent serum ones), and T3 treatment induced a downregulation of the hypothalamic AMPK pathway, this supporting the existence of a central contribution to the observed metabolic effects. These results may be relevant to the ongoing discussion in the clinical setting on thyroid hormone replacement therapy with T4, T3 or both combined in.