The hypothalamus–pituitary–thyroid (HPT) axis represents a classical example of an endocrine feedback loop. This review discusses dynamic changes in HPT axis setpoint regulation, identifying their molecular and cellular determinants, and speculates about their functional role. Hypothalamic thyrotropin-releasing hormone neurons were identified as key components of thyroid hormone (TH) setpoint regulation already in the 1980s, and this was followed by the demonstration of a pivotal role for the thyroid hormone receptor beta in negative feedback of TH on the hypothalamic and pituitary level. Gradually, the concept emerged of the HPT axis setpoint as a fixed entity, aiming at a particular TH serum concentration. However, TH serum concentrations appear to be variable and highly responsive to physiological and pathophysiological environmental factors, including the availability or absence of food, inflammation and clock time. During food deprivation and inflammation, TH serum concentrations decrease without a concomitant rise in serum TSH, reflecting a deviation from negative feedback regulation in the HPT axis. Surprisingly, TH action in peripheral organs in these conditions cannot be simply predicted by decreased serum TH concentrations. Instead, diverse environmental stimuli have differential effects on local TH metabolism, e.g. in liver and muscle, occurring quite independently from decreased TH serum concentrations. The net effect of these differential local changes is probably a major determinant of TH action at the tissue level. In sum, hypothalamic HPT axis setpoint regulation as well as TH metabolism at the peripheral organ level is flexible and dynamic, and may adapt the organism in an optimal way to a range of environmental challenges.
Eric Fliers, Andries Kalsbeek and Anita Boelen
Jacqueline E Siljee, Unga A Unmehopa, Andries Kalsbeek, Dick F Swaab, Eric Fliers and Anneke Alkemade
The melanocortin 4 receptor (MC4R) is an essential regulator of energy homeostasis and metabolism, and MC4R mutations represent the most prevalent monogenetic cause of obesity in humans known to date. Hypothalamic MC4Rs in rodents are well characterized in neuroanatomical and functional terms, but their expression pattern in the human hypothalamus is unknown.
Design and methods
To determine the topographic distribution and identity of cells expressing MC4R mRNA in the human hypothalamus, locked nucleic acid in situ hybridization was performed on nine human postmortem hypothalami. In addition, co-expression of MC4R with glial fibrillary acidic protein (GFAP), vasopressin/oxytocin (AVP/OXT), corticotropin-releasing hormone (CRH), neuropeptide Y (NPY), agouti-related protein (AgRP), and α-melanocyte stimulating hormone (α-MSH) was examined.
Most intense MC4R mRNA expression was present in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and the nucleus basalis of Meynert. Most MC4R-positive cells in the SON also expressed AVP/OXT. Co-expression with AVP/OXT in the PVN was less abundant. We did not observe co-expression of MC4R mRNA and GFAP, CRH, NPY, AgRP, or α-MSH. However, fiber-like staining of NPY, AgRP, and α-MSH was found adjacent to MC4R-positive cells in the PVN.
Expression of MC4R mRNA in the human hypothalamus is widespread and in close approximation to endogenous MC4R binding partners AgRP and α-MSH.
Edith C H Friesema, Theo J Visser, Anke J Borgers, Andries Kalsbeek, Dick F Swaab, Eric Fliers and Anneke Alkemade
Thyroid hormone (TH) signaling in brain cells is dependent on transport of TH across the plasma membrane followed by intracellular deiodination and binding to the nuclear TH receptors. The aim of this study is to investigate the expression of the specific TH transporters monocarboxylate transporter 8 (MCT8 (SLC16A2)), MCT10, organic anion transporting polypeptide 1C1 (OATP1C1 (SLCO1C1)), and the types 2 and 3 deiodinases (D2 and D3) in the developing human hypothalamus.
Fifteen postmortem brain samples of fetuses and young children ranging between 17 weeks of gestation and 29 months of postnatal age including one child (28 months) with central congenital hypothyroidism were studied.
Sections of the different hypothalami were stained with polyclonal rabbit antisera against MCT8, MCT10, OATP1C1, D2, and D3.
We found MCT8 and D3 but not D2 protein expression to be present in our earliest sample of 17 weeks of gestation, indicating triiodothyronine degradation, but not production at this time of development. At term, expression of TH transporters and D2 decreased and D3 expression increased, suggesting decreased TH signaling just before birth. The child with central congenital hypothyroidism showed higher MCT8 and D2 expression compared with the other children of similar age.
This study reports the developmental timing of expression of components crucial for central TH signaling in the human hypothalamus. In general, during fetal hypothalamic development, the coordinated expression of D2 and D3 in combination with the different TH transporters suggests that proper TH concentrations are regulated to prevent untimely maturation of brain cells.
Charlotte A Heinen, Zhi Zhang, Lars P Klieverik, Tim C de Wit, Edwin Poel, Maqsood Yaqub, Anita Boelen, Andries Kalsbeek, Peter H Bisschop, A S Paul van Trotsenburg, Hein J Verberne, Jan Booij and Eric Fliers
Brown adipose tissue (BAT) activity in humans is stimulated by cold and by a limited number of pharmacological agents, including β3-adrenergic agonists and bile acids. Although thyrotropin-releasing hormone (TRH) is known to activate BAT in several mammals, this has not been reported in humans.
A randomized, placebo-controlled, double-blind, cross-over trial.
We investigated the effects of intravenous bolus administration of 400 µg TRH or 2 mL saline on BAT activity in healthy, lean men. BAT activity was measured as standardized 18F-fluorodeoxyglucose (18F-FDG) uptake and glucose metabolic rate (MRglu) using dynamic PET/CT imaging. The first six individuals were studied at room temperature, while subsequently nine were exposed to mild cold (17°C ± 1°C) for 60 min before imaging. During the dynamic scan, blood was withdrawn for measurement of thyroid hormone and catecholamine concentrations. This trial is registered with The Netherlands National Trial Register (number NTR5512).
Sixteen participants were recruited. Six men studied at room temperature showed no visible BAT activity during either session. After exposure to mild cold, four of nine men (44.4%) showed clear increase of 18F-FDG uptake after TRH administration compared to placebo. Maximal standardized 18F-FDG uptake showed a trend toward increase after TRH compared to placebo (P = 0.066). MRglu showed a significant increase after TRH administration (P = 0.014). The increase in 18F-FDG uptake was not paralleled by changes in plasma thyroid hormone or catecholamine concentrations.
Systemic TRH administration can increase the activity of cold-stimulated BAT in adult men. These findings may assist developing pharmacological strategies for modulating BAT activity in the management of obesity.