Mechanisms in Endocrinology: Beyond the fixed setpoint of
Geplaatst: za 11 okt 2014, 12:55Volledig artikel (Nederlands onderzoek)
Journal of the European Society of Endocrinology
Mechanisms in Endocrinology: Beyond the fixed setpoint of the hypothalamus–pituitary–thyroid axis
Eur J Endocrinol November 1, 2014 171 R197-R208
Eric Fliers1, Andries Kalsbeek1,2 and Anita Boelen1
1Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, 1105 AZ
Amsterdam, The Netherlands and 2Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
Abstract
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.
Een paar stukjes:
Local TH metabolism "
A number of molecular
determinants, including transporters and enzymes, are
critical for local TH bioavailability. THs have to be
transported into cells in order to be able to exert their
effects. In the human hypothalamus, three types of TH
transporters have been reported: the organic anion
transporting polypeptide 1C1 (OATP1C1), which preferentially
transports T4, and the monocarboxylate
transporter 8 (MCT8) and MCT10, facilitating both the
uptake and efflux of T3 and T4 (14, 15, 16). Once
transported into the cell, only T3 binds
Thyroid gland and peripheral organs
TH production by the thyroid gland is mainly regulated by
TSH via binding to the TSHR on the follicular thyrocyte.
Activation of the TSHR stimulates a variety of processes
involved in TH synthesis, ultimately resulting in the
release of T4 (the prohormone) and T3 (the active
hormone) from thyroglobulin (41). In healthy individuals,
20% of daily T3 production is secreted by the thyroid
gland, whereas 80% is generated extrathyroidally by
iodothyronine deiodinases (42). Once released, T4 and T3
circulate in the bloodstream bound to serum proteins
including thyroid hormone-binding globulin, transthyretin,
and albumin. Over 99% of serum THs is bound,
leaving w1% of TH as freely available for uptake by target
tissues. As mentioned earlier, TH are actively transported
into cells in order to exert their effects, while the prohormone
T4 needs to be converted into the active
hormone T3 by deiodinating enzymes (17). It has been
thought for many years that liver D1 is critical for release
of T3 into the circulation, but more recent studies have
suggested that liver D1 is more important for TH clearance
in the hyperthyroid state (43). Its expression is positively
regulated by T3 (44, 45).
In the last few years, polymorphisms of deiodinating
HPT axis setpoint regulation: examples of physiological determinants
Clock time
One of the physiological determinants known to affect the
HPT-axis is clock time: serum TSH is low during daytime,
starts to increase in the early evening and peaks around
the beginning of the sleep period. This phenomenon is
known as the nocturnal TSH surge in humans (61, 62). The
diurnal TSH rhythm is generated by the hypothalamic
SCN, which is the biological clock of the brain, as
Acute inflammation
Acute inflammation is known to induce profound
alterations in both circulating serum TH levels and tissue
TH metabolism. Although the inflammation-induced
alterations in local TH metabolism have not been studied
extensively in humans, major surgery – an example of
acute NTIS – induces a rapid inflammatory response
characterised by activation of neutrophils and the release
of a variety of proinflammatory cytokines (73, 74, 75).
Simultaneously, significant alterations in serum T3, T4 and
rT3 concentrations and in T3/rT3 and T3/T4 ratios are
observed, suggesting impaired TH conversion. Experimental
studies in rodents have shown that
Conclusion
Under basal conditions, the HPT axis is regulated by
negative TH feedback at the hypothalamic and pituitary
level, resulting in stable circulating FT4 concentrations.
However, a number of environmental challenges induce
complex interactions of novel players, including D2
in hypothalamic tanycytes, which result in a net TH
setpoint change. For example, during food deprivation
and inflammation, TH serum concentrations decrease
without a concomitant rise in serum TSH. Surprisingly,
TH action at the tissue level in these conditions is not a
simple reflection of decreased TH serum concentrations.
Instead, there appear to be differential effects on local TH
metabolism in liver and muscle, which occur quite
independently from TH serum concentrations. In sum,
hypothalamic HPT axis setpoint regulation as well as TH
metabolism at the peripheral organ level appear to be
dynamic, and may help to adapt the organism to a range
of environmental challenges.
Zie volledig met figuren:
http://www.eje-online.org/content/171/5/R197.full.pdf
Journal of the European Society of Endocrinology
Mechanisms in Endocrinology: Beyond the fixed setpoint of the hypothalamus–pituitary–thyroid axis
Eur J Endocrinol November 1, 2014 171 R197-R208
Eric Fliers1, Andries Kalsbeek1,2 and Anita Boelen1
1Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, 1105 AZ
Amsterdam, The Netherlands and 2Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
Abstract
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.
Een paar stukjes:
Local TH metabolism "
A number of molecular
determinants, including transporters and enzymes, are
critical for local TH bioavailability. THs have to be
transported into cells in order to be able to exert their
effects. In the human hypothalamus, three types of TH
transporters have been reported: the organic anion
transporting polypeptide 1C1 (OATP1C1), which preferentially
transports T4, and the monocarboxylate
transporter 8 (MCT8) and MCT10, facilitating both the
uptake and efflux of T3 and T4 (14, 15, 16). Once
transported into the cell, only T3 binds
Thyroid gland and peripheral organs
TH production by the thyroid gland is mainly regulated by
TSH via binding to the TSHR on the follicular thyrocyte.
Activation of the TSHR stimulates a variety of processes
involved in TH synthesis, ultimately resulting in the
release of T4 (the prohormone) and T3 (the active
hormone) from thyroglobulin (41). In healthy individuals,
20% of daily T3 production is secreted by the thyroid
gland, whereas 80% is generated extrathyroidally by
iodothyronine deiodinases (42). Once released, T4 and T3
circulate in the bloodstream bound to serum proteins
including thyroid hormone-binding globulin, transthyretin,
and albumin. Over 99% of serum THs is bound,
leaving w1% of TH as freely available for uptake by target
tissues. As mentioned earlier, TH are actively transported
into cells in order to exert their effects, while the prohormone
T4 needs to be converted into the active
hormone T3 by deiodinating enzymes (17). It has been
thought for many years that liver D1 is critical for release
of T3 into the circulation, but more recent studies have
suggested that liver D1 is more important for TH clearance
in the hyperthyroid state (43). Its expression is positively
regulated by T3 (44, 45).
In the last few years, polymorphisms of deiodinating
HPT axis setpoint regulation: examples of physiological determinants
Clock time
One of the physiological determinants known to affect the
HPT-axis is clock time: serum TSH is low during daytime,
starts to increase in the early evening and peaks around
the beginning of the sleep period. This phenomenon is
known as the nocturnal TSH surge in humans (61, 62). The
diurnal TSH rhythm is generated by the hypothalamic
SCN, which is the biological clock of the brain, as
Acute inflammation
Acute inflammation is known to induce profound
alterations in both circulating serum TH levels and tissue
TH metabolism. Although the inflammation-induced
alterations in local TH metabolism have not been studied
extensively in humans, major surgery – an example of
acute NTIS – induces a rapid inflammatory response
characterised by activation of neutrophils and the release
of a variety of proinflammatory cytokines (73, 74, 75).
Simultaneously, significant alterations in serum T3, T4 and
rT3 concentrations and in T3/rT3 and T3/T4 ratios are
observed, suggesting impaired TH conversion. Experimental
studies in rodents have shown that
Conclusion
Under basal conditions, the HPT axis is regulated by
negative TH feedback at the hypothalamic and pituitary
level, resulting in stable circulating FT4 concentrations.
However, a number of environmental challenges induce
complex interactions of novel players, including D2
in hypothalamic tanycytes, which result in a net TH
setpoint change. For example, during food deprivation
and inflammation, TH serum concentrations decrease
without a concomitant rise in serum TSH. Surprisingly,
TH action at the tissue level in these conditions is not a
simple reflection of decreased TH serum concentrations.
Instead, there appear to be differential effects on local TH
metabolism in liver and muscle, which occur quite
independently from TH serum concentrations. In sum,
hypothalamic HPT axis setpoint regulation as well as TH
metabolism at the peripheral organ level appear to be
dynamic, and may help to adapt the organism to a range
of environmental challenges.
Zie volledig met figuren:
http://www.eje-online.org/content/171/5/R197.full.pdf