Abstract
Besides their direct effects on peripheral metabolic tissues, thyroid hormones (TH) act on the hypothalamus to modulate energy homeostasis. However, since most of the hypothalamic actions of TH have been addressed in studies with direct central administration, the estimation of the relative contribution of the central vs. peripheral effects in physiologic conditions of peripheral release (or administration) of TH remains unclear. 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 status and relate them to the metabolic effects of the treatment. Peripheral TH treatment affected feeding behavior, overall growth, core body temperature, body composition, brown adipose tissue (BAT) morphology and uncoupling protein 1 (UCP1) levels and metabolic activity, white adipose tissue (WAT) browning and liver metabolism. This resulted in an increased overall uncoupling capacity and a shift of the lipid metabolism from WAT accumulation to BAT fueling. Both peripheral treatment protocols induced significant changes in TH concentrations within the hypothalamus, with T3 eliciting a downregulation of hypothalamic AMP-activated protein kinase (AMPK), supporting the existence of a central action of peripheral TH. Altogether, these data suggest that peripherally administered TH modulate energy balance by various mechanisms; they also provide a unifying vision of the centrally mediated and the direct local metabolic effect of TH in the context of hyperthyroidism.
Highlights
The relationship between thyroid hormones’ (TH; T3: triiodothyronine and T4: thyroxine) status and whole-body energy balance was the described as early as the end of the 19th century [1], with numerous clinical examples in patients with thyroid dysfunction [2,3].Hyperthyroidism and/or thyrotoxicosis induce a hypermetabolic state with a raising basal metabolic rate (BMR) and feeding-independent weight loss [2,4,5,6,7]
In the brown adipose tissue (BAT), TH increase the stimulatory action of noradrenaline (NE) and enhance the cAMP-mediated rise in uncoupling protein 1 (UCP1) mRNA expression [7,9,10,11,12]
The discovery of the central TH action on body metabolism challenged the classical The discovery of the central TH action on body metabolism challenged the classical view of the peripheral effects of these hormones
Summary
Hyperthyroidism and/or thyrotoxicosis induce a hypermetabolic state with a raising basal metabolic rate (BMR) and feeding-independent weight loss [2,4,5,6,7]. TH action in the metabolic organs have been identified. In the brown adipose tissue (BAT), TH increase the stimulatory action of noradrenaline (NE) and enhance the cAMP-mediated rise in uncoupling protein 1 (UCP1) mRNA expression [7,9,10,11,12]. TH effects on core body temperature, body composition and white adipose tissue (WAT) browning have been described [10,18,19,20,21,22]
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