Central vs. Peripheral Action of Thyroid Hormone in Adaptive Thermogenesis: A Burning Topic

Abstract

Thyroid hormones (TH) contribute to the control of adaptive thermogenesis, which is associated with both higher energy expenditure and lower body mass index. While it was clearly established that TH act directly in the target tissues to fulfill its metabolic activities, some studies have rather suggested that TH act in the hypothalamus to control these processes. This paradigm shift has subjected the topic to intense debates. This review aims to recapitulate how TH control adaptive thermogenesis and to what extent the brain is involved in this process. This is of crucial importance for the design of new pharmacological agents that would take advantage of the TH metabolic properties.

Keywords: brown adipose tissue; browning; hypothalamus; thermogenesis; thyroid hormones.

Figure 1

The main actors of adaptive thermogenesis and their principle thermogenic mechanisms. Adipose tissues and muscles are the main actors of adaptive thermogenesis. White adipocytes are not thermogenic per se but can undergo browning to generate beige adipocytes. Bottom left panel: Brown and beige adipocytes use free fatty acids (FFA) to fuel the mitochondrial β-oxidation. β-oxidation generates reduced compounds (NADH, FADH₂) whose oxidation is used by the respiratory electron transport chain (complex I, II, III, IV) to pump protons (H⁺) into the intermembrane space. Thus, an electrochemical gradient is created and used by ATP synthase to produce ATP. UCP1 is present in the inner mitochondrial membrane and activated by FFA. UCP1 acts as a proton channel to dissipate the electrochemical gradient without producing ATP. Thus, to match the inefficient ATP production, the metabolism must increase and heat is produced. Bottom right panel: Myocytes express SERCA that is located in the sarcoplasmic reticulum (SR) membrane. SERCA transfers calcium (Ca²⁺) from the cytosol to SR lumen using ATP hydrolysis. The calcium gradient generated by SERCA is dissipated by ryanodine receptor (RyR1). SERCA transport activity can be inhibited by two peptides: phospholamban (PLP) or sarcolipin (SLN), but its ATPase activity remains. To match Ca²⁺ transport, ATP mitochondrial synthesis increases and heat is produced.

Figure 2

Control of brown adipocyte UCP1-dependent thermogenesis by norepinephrine and thyroid hormone. Sympathetic neurons release synaptic norepinephrine that binds to β-adrenergic receptors (β-AR) coupled to stimulatory guanine nucleotide binding protein (Gs) which activates adenylate cyclase (AC) to produce cAMP. This adrenergic signaling activates transcription factors (TF) and coactivators involved in the regulation of D2. Both adrenergic signaling and thyroid hormone receptors (TRs) regulate Ucp1 expression. Triglycerides are broken down into free fatty acids by lipases and transported to mitochondria to fuel the β-oxidation and activate UCP1. UCP1 uncouples ATP production from respiration, requiring an increased mitochondrial activity and heat is produced.

Figure 3

The different views for TH-induced adaptive thermogenesis. In the classical « peripheral » view (left panel), TH (red dots) are produced by the hypothalamic-pituitary-thyroid axis. TH are then released in the blood (red arrows) and are transported to targeted tissues. Then, they locally act on their receptors to trigger BAT and muscle thermogenesis, as well as WAT browning. This paradigm has been challenged by the description of a central mode of TH action to trigger adaptive thermogenesis (right panel). In this view, TH reaching the ventromedial medial hypothalamus decreases AMPKα phosphorylation in this region, alleviating endoplasmic reticulum (ER) stress. It leads to an increased sympathetic nervous system (SNS) output (axons drawn in blue) and the release of synaptic norepinephrine (blue dots) to trigger both BAT thermogenesis and WAT browning. However, no evidence as so far been brought to consider a TH-central control of muscle adaptive thermogenesis.