Where is thyrotropin releasing hormone produced

Thus, the coordinated regulation of PCs may play an important role in neuroendocrine cells in maintaining a proper enzyme-substrate homeostasis, and ensuring adequate processing of newly synthesized prohormones Fig. The different hormonal inputs regulating the PCs are also represented. At the cellular level, changes in the thyroid status also have an effect on the processing of proTRH by altering the level of PCs [ ; ].

In the PVN of hypothyroid rats, an increase for the end products of proTRH processing analyzed peptides was found [ ]. This finding was further supported by studies demonstrating that the PC promoters contain thyroid receptors, which can be negatively regulated by thyroid hormone [ ; ; ]. Thus, regulation of prohormone and enzyme by changes in thyroid status may lead to altered hormonal biosynthesis.

This regulation represents a novel aspect in the way the HPT axis is integrated between the central and peripheral inputs, which may have important implications in the pathophysiology of hypo- and hyperthyroidism Figs. At the central level, the hypothalamus is the primary component of the nervous system in interpreting adiposity or nutrient related inputs; it delivers hormonal and behavioral responses with the ultimate purpose of regulating energy intake and consumption.

At the molecular level, enzymes called nutrient or energy sensors mimic the role of the tissues involved in energy balance [ ]. TRH neurons represent the second order of neurons when stimulated by the melanocortin system. The fall in circulating levels of the hormone leptin during starvation is the signal to the brain that suppresses preproTRH expression in the PVN.

Serum leptin decreases considerably during fasting, and leptin replacement during a hour fast partly prevents the fasting-induced decrease in serum T4 and increase in serum corticosterone in mice. In turn, leptin was proposed as a vital signal that initiates the neuroendocrine response to fasting [ ]. Initially considered as a hormone to prevent obesity, it was later showed that the major role of leptin is to signal the switch from the fed to the starved state at the hypothalamic level [ ; ; ].

The fall in circulating levels of leptin is perceived in the hypothalamus to increase appetite, decrease energy expenditure, and change neuroendocrine function in a direction that favors survival. The major consequences of falling leptin include activation of the stress axis, and suppression of reproduction, linear growth, and the thyroid axis [ ].

In summary, leptin has a central physiologic role in providing information on energy stores and energy balance to brain centers that regulate appetite, energy expenditure and neuroendocrine function [ ; ; ; ; ]. When leptin signaling is deficient, due either to mutation of leptin peptide or leptin receptor genes, severe obesity results in both rodents and humans [ ; ; ; ; ], underscoring the fundamental role of leptin in the physiology of energy balance. Although the hypothalamic effects of leptin are mediated via the hypothalamic melanocortin system, which plays an essential role in feeding behavior, two landmark studies demonstrated the existence of a direct effect of leptin on TRH neurons [ 16 ; 17 ].

These studies showed that leptin dose-dependently stimulated the increase in proTRH biosynthesis and TRH release in primary cultures of hypothalamic neurons [ 17 ]. It was also demonstrated that STAT3 mediates the transcriptional effects of leptin in vivo suggesting that the TRH promoter is directly regulated by leptin [ 71 ].

Leptin rapidly regulates polarization of neurons in isolated brain slices of the PVN and can stimulate TRH peptide release from dispersed hypothalamic cultures and hypothalamic tissue ex vivo [ 17 ; 55 ]. Leptin produced a five-fold induction of luciferase activity in CV-1 cells transfected with a TRH promoter-luciferase reporter and the long form of the leptin receptor cDNA [ 16 ].

Additionally, peripheral administration of leptin to rodents activates SOCS-3 suppressor-of-cytokine-signaling mRNA which is the sensitive marker of direct leptin action in neurons located in the PVN [ 16 ; ]. This question was recently clarified where it was determined that leptin affects both pathways [ 16 ; 18 ; ; ; ], providing compelling evidence in support of the direct action of leptin on TRH neurons.

Two additional findings support the existence of the direct pathway, 1 MC4-R KO mouse and patients with MC4-R mutations have normal thyroid hormone levels [ ; ], 2. Using nuclear P-CREB staining and a pharmacological antagonist of MC4-R, it was shown that the melanocortin system has a primary role in the leptin-mediated activation of hypophysiotropic proTRH neurons [ 18 ].

This diagram shows the two subgroups of TRH neurons recently identified based on their signaling modalities. Other neurons stimulated by the melanocortin pathway might be involved in sympathetic activity or food intake regulation.

NPY may regulate TRH neurons through mechanism 1 or 2 depending upon the status of the melanocortin system. Previous data suggest that the primary action of leptin on the HPT axis is exclusively mediated by hypothalamic ARC neurons through direct axonal projections to the PVN.

It was proposed that if the ARC is ablated by neonatal treatment with mono-sodium glutamate MSG , not only is the response of the thyroid axis to fasting abolished, but its response to the exogenous administration of leptin is lost as well [ ].

However, this is not the ideal model to test this hypothesis. Rats subjected to neonatal MSG are less sensitive to peripherally administered leptin [ ; ]. Moreover, since MSG treatment causes lesions to blood-brain barrier-free areas, it is possible that the leptin insensitivity is due to an impaired leptin transport system rather than lesions of specific leptin-sensitive cells.

The complex metabolic disturbances of MSG rats hyperinsulinaemia, hypercorticosteronaemia, hyperleptinaemia, hyperglycaemia could contribute significantly to the peripheral leptin resistance observed by Dawson et al. Hyperleptinemia observed in MSG treated rats was sustained for at least days of age [ ] indicating that the administration of leptin to MSG treated rats will not have an effect on the HPT axis because the animals are already leptin resistant.

It was early suggested that NPY, in parallel with triggering feeding behavior, interrupts normal thyroid feedback during food deprivation. An early study showed that NPY and catecholaminergic inputs on TRH neurons are of mixed origin, and those cell bodies and proximal dendrites of TRH neurons receive a robust, putative inhibitory NPY input from the hypothalamus [ ].

There are at least 6 NPY receptors subtypes, but Y1 and Y5 have received specific attention because of their ability to increase food intake when specifically stimulated [ ]. It is unknown the degree that Y1 and Y5 are present within the same neuron in the PVN or ARC, but in other regions these receptors have been seen individually in separate neurons or colocalized [ ].

Y1 specific agonists stimulate the appetite phase of food intake, while Y5 specific agonists stimulate the meal size and duration during food intake [ ]. Y1 but not Y5 antagonists block the effects of NPY on food intake in rats. Fasting-induced food intake was reduced in Y1 but not Y5 knockout mice [ ]. Therefore, it is tempting to speculate that NPY downregulation on TRH neurons will occur by two different pathways or mechanisms, similar to what it is was shown for leptin.

The physiological role of the thyroid goes beyond maintaining the basic metabolic rate in all cells. A common situation in which thyroid hormone levels are subject to major physiological changes is during the transition from the fed to the starved state. Starvation is a severe threat to survival, and in rodents, the capacity to survive without food can be measured in a matter of days.

Given that thyroid hormone has the ability to set the basal metabolic rate, a suppression of thyroid hormone during starvation reduces metabolic rate and preserves energy stores.

Since animals in the wild commonly experience periods of starvation, the thyroid response to starvation should be considered as a major evolutionary mechanism designed to ensure survival when food is scarce. Through evolution, primitive humans faced long periods of food scarcity and starvation, and those who survived these conditions adapted their evolutionary traits to provide a greater capacity for conserving energy in fat stores until food became available again.

However, these properties that in the past constituted an evolutionary advantage, today make humans more susceptible to become obese during times of large quantities of available food. Undeniably, this prosperous genotype in modern and industrialized societies, characterized by food abundance and reduced physical activity, culminated in an obesity of gigantic proportions, mostly in developed countries [ ; ; ].

How does this nutritional adaptation take place? The thyroid system has several levels of regulation beginning at the level of the hypothalamus. There is a tightly regulated relationship to maintain homeostatic concentrations of thyroid hormones, by activating the feedback mechanisms on the biosynthesis of proTRH in the PVN followed by the pulsatile secretion of TRH from the ME [ 26 ; ].

However, during starvation this dynamic is completely altered. Starvation suppresses hypophysiotropic preproTRH gene expression, while other TRH producing neurons inside or outside the hypothalamus are not affected [ ].

Such a decrease in circulating thyroid hormone levels is associated with a reduction in the biosynthesis of TRH and the secretion of TSH [ ; ; ]. By creating this state of central hypothyroidism, the resulting reduction in thyroid stimulating thermogenesis may serve as an important energy conservation mechanism until re-feeding occurs. How and where does the signal to the brain coordinate this adaptation? It was suggested that reduced TRH secretion might be due to the fasting-induced increase of corticosterone [ ; ].

The reason for this alteration is that TRH neurons are strongly affected by the nutritional status of the animal, which is similar in humans. This discovery adds a new level of understanding of the evolutionary role of the HPT axis, which involves an environmental adaptation to preserve energy during periods of malnourishment. We now know that the response to starvation not only causes changes in carbohydrate and fat metabolism, but also affects several neuroendocrine axes [ 26 ; ].

How do thyroid hormones produced in the thyroid gland regulate these processes throughout the body [ 77 ; : Nillni, ] to maintain homeostasis at a constant rate? Performing work or generating heat in different ways can be the source for spending energy in the form of thermogenesis. Adaptive thermogenesis or regulated production of heat is affected by environmental temperature and diet. The mitochondria organelles that convert food to carbon dioxide, water and ATP, are fundamental in mediating effects on energy dissipation.

Thyroid hormone-dependent energy expenditure is related to adaptive or facultative thermogenesis, which is characterized by an uncoupling of oxidative phosphorylation in cold-exposed brown adipose tissue BAT dependent on locally generated thyroid hormone. For example, shivering reaction during cold exposure uses energy and this is an example of adaptive thermogenesis. In small mammals, sympathetic adrenergic stimulation of BAT induces uncoupling protein-1 UCP- 1 that uncouples the mitochondrial proton gradient from ATP production promoting the generation of heat.

A major contributor in this reaction is D2, which increases local, intracellular T3 production from T4 [ ] Fig. The important central role of D2 in the generation of T 3 in cold-induced BAT thermogenesis was demonstrated by a blocked in non-shivering thermogenesis in response to cold exposure [ ] giving an important role to the interaction between the adrenergic sympathetic innervation cascade and thyroid hormone action [ 10 ; 11 ].

In humans, skeletal muscle plays the thermogenic role accomplished by brown adipose tissue in small mammals, a tissue that contains sufficient mass, innervation, and metabolic activity. Therefore, a prominent portion of the basal metabolic rate activity among normal humans could be assigned to this tissue alone [ ]. The family of deiodinases converts less active T 4 to the more active T 3 or inactive reverse T 3 in various tissue sites.

Since the hypothalamic TRH expression is regulated by T 3 via negative feedback inhibition the availability of T 3 converted from T 4 is of key importance in this regulation. Several deiodinases are involved in the production of T 3 in a tissue-specific manner.

D2 is expressed in the central nervous system, the anterior pituitary, and brown adipose tissue Fig. This unique signaling modality plays an important role in thyroid feedback on TRH cells [ ]. Hypothyroid and fasted rats show elevated hypothalamic D2 mRNA and D2 activity, and while T 4 administration restores D2 mRNA expression in hypothyroid rats, it does not restore the fasting-induced increase of D2 expression, suggesting that the elevation of D2 production and activity during fasting is not related to the thyroid [ ].

In another set of studies, the same group showed that hypothalamic D2 activity was not affected by either leptin or corticosterone administration in the fed state, but it was restored by leptin in the fasting state.

They concluded that a decrease in serum leptin seen during fasting plays an important role in the increased serum corticosterone concentrations to elevate D2 activity [ ]. Inhibition of D2 activity by ICV infusion of the deiodinase inhibitor iopanoic prevented the fasting-induced hypothalamic TRH decrease consistent with the observation that increased hypothalamic D2 activity during starvation may cause a higher production of local T 3 that in turn decreases the TRH expression in the PVN [ ].

There is also a possibility that leptin may regulate deiodinases in other tissues to alter the set point of the thyroid axis. Supporting this hypothesis, a previous study showed that central administration of leptin affected D2 activity in BAT through a possible activation of the sympathetic nervous system [ ]. This reaction resulted in a significant increase in plasma T 3 levels, a situation that favors the activity of hepatic D1, given the high sensitivity of this enzyme to T 3 [ ].

However, when these studies were performed there was no information about the role of leptin regulating the TRH neuron. Therefore, it remains to be confirmed what contribution each of these leptin targets have in controlling the synthesis of T3 during changes in nutritional status. When leptin levels are high, does T3 increase because of a leptin action on TRH neurons stimulating the HPT axis that, in turn, provides more T4 available for conversion by deiodinases to T3, or does leptin increase deiodinase activity in specific tissues to convert the existing T4 to T3, or indeed are both mechanisms involved?

The PPII enzyme is commonly expressed in tanycytes and glial cells lining the third ventricle in the hypothalamus. The cytoplasmic processes of these cells reach the median eminence suggesting that PPII regulates the output of TRH peptide from the ME before its reaches the pituitary. Long-term hypocaloric dietary regimens resulted in alterations similar to those observed during fasting. Although serum T3 and rT3 tended to return to basal concentrations during the last period of hypocaloric regime, TSH release upon TRH infusion remained low during the whole period, indicating that central and peripheral thyroid hormone metabolisms are affected via separate process [ ].

In an effort to understand whether the decreased in hypothalamic TRH secretion during fasting is responsible for the decrease in TSH, the effect of hour TRH infusion during a 6-day fast was investigated.

Another study determined the effect of fasting on circadian and pulsatile TSH secretion in eight healthy humans by measuring serum TSH every 10 minutes during the last 24 hours of a hour fast. The decreased nocturnal TSH surge during fasting was associated with a significantly decreased TSH pulse amplitude, but with an unaltered number of TSH pulses between h.

These results seem to indicate that fasting decreases h TSH secretion and the nocturnal TSH surge in the absence of a change in plasma T4 concentration [ ]. The discovery of leptin as an important regulator of the thyroid axis provided an additional insight about the multiple mechanisms regulating the thyroid axis [ ; ; ; ].

In humans, Chan et al. The administration of recombinant human leptin, prevented the fall in TSH secretion, suggesting that leptin regulates the alterations in TSH levels and TSH pulsatility during fasting [ ]. In a follow up study, the effects of a hour fast in healthy women resulted in a similar relative decrease of serum leptin, but exogenous leptin did not affect TSH pulsatility [ ], although leptin replacement during the 4-day fast did result in higher hour mean TSH concentrations compared to placebo [ ].

The thyroid axis responds at multiple levels to illness rendering inappropriate secretion of TSH, which is seen in non-thyroidal illness. Non-thyroidal illness is generally associated with anorexia, suggesting that the leptin and melanocortin signaling pathways may play a key role in this process.

A previous study suggested that central hypothyroidism associated with infection might be due to up-regulation of D2 activity in tanycytes present in the walls and floor of the third ventricle.

These cells could lead to inhibition of TRH gene expression by increasing local T 3 production [ ]. In the human hypothalamus postmortem , the HPT axis response to illness produced extensive changes. Consistent with this hypothesis, it was recently demonstrated that the biosynthesis of the TRH peptide in the PVN and its release from the ME is restored after the administration of leptin to fasted animals, independent of calorie intake [ ].

After leptin treatment in fasted animals, the T 4 values exceeded the normal values seen in fed control animals [ ]. The TSH levels, consistent with previous studies [ ], showed a small, but significant, decrease in male rats during fasting. It has been suggested previously that most of the TSH detected during fasting, in the absence of TRH, may not be functional.

TRH plays a key role in the glycosylation of TSH in thyrotrophs by regulating the posttranslational maturation of TSH oligosaccharide chains to promote full biological activity, which means that such a reduction in TRH leads to TSH with less complex carbohydrate structures and reduced bioactivity that can be restored by TRH administration [ ]. Humans with central hypothyroidism hypothalamic disease frequently have normal, or even slightly higher, serum TSH concentrations.

These patients with hypothalamic diseases showed poor glycosylation of TSH, which is mannose-rich compared to control and primary hypothyroid patients. Similar studies done in humans were consistent with these findings. Rosenboun et al [ ] found that in clinical studies maintenance of reduced body weight was associated with decreased hour energy expenditure, a decrease in circulating plasma concentration of leptin, and thyroid hormones.

All these endocrine changes were reversed by administration of replacement doses of leptin. The conclusion from studies done in animals and humans support the hypothesis that the neuroendocrine changes associated with constant reduced body weight are due, partially, to the lower circulating levels of leptin secondary to reduced fat mass. It is clear now that nutritional regulation of the thyroid axis through TRH in rodents and humans is important to both food deprivation and to illness.

Humans with mutations of the ObRb have central hypothyroidism [ ]. Also, controlled caloric restriction in humans, which leads to weight loss, results in a decline in serum T 3 levels, which can be reversed by leptin [ ]. On the other hand, acute fasting in humans leads to a loss in the normal pulsatile release of TSH, a situation that can be reversed by leptin replacement [ ; ]. Humans with MC4-R mutations have an obese phenotype, however, they have a normal thyroid axis [ ; ; ; ]. Some patients with central hypothyroidism of hypothalamic origin are associated with the secretion of TSH molecules, but decreased bioactivity because of changes in the oligosaccharide chains [ ].

Obesity and its related medical complications including type 2 diabetes, cardiovascular disease, dyslipidemia, and cancer account for more than , deaths per year in the United States.

Obesity treatment strategies often do not result in adequate sustained weight loss, and the prevalence and severity of obesity in the U.

Recent surveys classify roughly one third of all Americans as obese [ ]. The complexity of the obesity condition results from the interaction between environmental and predisposed genetic factors [ ]. A more thorough understanding of the molecular mechanisms underlying the pathogenesis of obesity and regulation of energy metabolism is essential for the development of effective therapies.

Obesity occurs as a result of a longstanding imbalance between energy intake and energy expenditure, which is influenced by a very complex set of biological pathway systems regulating appetite [ ; ; ; ].

A better understanding of the causes of obesity lies in uncovering the molecular and physiologic mechanisms that regulate appetite, satiety, and energy balance [ ; ; ; ; ; ; ] and will further improve the possibility to develop new anti-obesity drugs. The interaction between the thyroid axis and development of obesity in humans is characterized by a complex relationship between leptin and hypothalamic TRH with important connotations in the thyroid status [ ].

Different from insulin or cortisol, which fluctuate in response to nutritional changes and stress, thyroid hormones are typically maintained at a constant level, keeping the metabolic machinery running at a proper metabolic rate [ : Nillni, ].

Thyroid hormones are crucial for the survival of both rodents and humans by adjusting its levels from fed to starved state where in the case of starvation a rapid suppression of T4 and T3 levels occurs to preserve energy stores. The secretion of T 3 and T 4 is controlled by a feedback system involving the pituitary gland and hypothalamus that produces hormones that regulate thirst, hunger, body temperature, sleeps, moods and sex drive.

When plasma levels of thyroid hormone fall, the biosynthesis and secretion of hypophysiotropic TRH increase, raising the threshold for feedback inhibition by thyroid hormone on anterior pituitary thyrotrophs, and thus increasing TSH secretion.

Conversely, elevations in plasma concentrations of thyroid hormone suppress the biosynthesis and secretion of TRH, causing a reduced threshold for feedback regulation by thyroid hormone on thyrotrophs resulting in suppression of TSH secretion, thus leading to a reduced release of thyroid hormones [ 19 ].

Changes of thyroid function are associated with changes in both body weight and energy expenditure, but despite intensive research in this area, results are still not very clear on the role of leptin in thyroid pathophysiology [ ].

Patients with thyroid disease usually have secondary disturbances of body weight, food intake and thermogenesis [ ]. In healthy adults, plasma TSH and leptin concentrations are synchronized, suggesting that leptin regulates the HPT axis in humans [ ; ]. Patients with leptin receptor mutations or leptin deficiency show features of hypothalamic hypothyroidism [ ; ], and leptin treatment increases plasma thyroid hormones in leptin deficient humans [ ].

Also, leptin administration reverses the low thyroid hormones in subjects on hypocaloric diets [ ]. Based on these observations, one would expect to find high activity of the HPT axis in hyperleptinemic obese subjects.

Although this has not been consistently observed, several studies reported that obese individuals have a higher activity of thyroid axis within the normal range [ ; ; ; ; ]. Patients with morbid obesity have higher levels of thyroid hormones compared to normal weight subjects [ ].

Therefore, it is possible that this model of leptin-induced resetting of the hypothalamic thyrostat may explain the alteration of the thyroid axis found in, at least, a subpopulation of obese individuals. Intriguingly, most obese humans and rodents have high levels of plasma leptin, which neither reduces appetite nor increases energy expenditure [ ; ].

This condition of hyperleptinemia is known as leptin resistance. While the neuronal circuits controlling food intake and energy expenditure in lean and obese animals have been extensively investigated [ ; ], the neuronal circuits controlling the HPT axis in obese animals are poorly understood. Even with high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects.

These observations underscore the physiological significance of leptin sensing in the melanocortin circuits and show that loss of leptin sensitivity contributes to the pathology of leptin resistance.

Therefore, it appears that leptin resistant is only a temporary phenomena. So even when overweight humans are likely to be leptin resistant, this condition can improve by losing weight. This circumstance is quite different to type 2 diabetes and insulin resistance, which is very hard to reverse, while leptin resistance is fairly correctable with a normal, healthy diet and exercise. Previous studies have shown that pretreatment of fasted rats with a melanocortin antagonist fully blocks the leptin-induced effect on the HPT axis [ 18 ] demonstrating that this neuronal pathway is heavily implicated in the activation of the HPT axis.

This intriguing observation suggests that the direct pathway of leptin action on TRH neurons could play a significant role during the stage of leptin resistance to maintain the overall homeostasis. Confirming these initial observations, DIO rats, similarly to lean animals, down-regulated the HPT axis during fasting. In the absence of a functional melanocortin system, which is the case of the DIO rat, the TRH synthesis in the MC4KO mice during fasting or administration of leptin was similar to wild type animals [ ].

To further test the hypothesis that the higher plasma T3 levels seen in DIO rats occur because of direct leptin action, fed Zucker rats Zucker rats bear a mutation in the leptin receptor gene and lacks leptin response [ ; ] with regular chow or HFD were unable to increase the levels of T3 seen in regular DIO rats. This finding confirms the notion that higher levels of plasma T3 seen in DIO rats depends, at least in part, on leptin signaling unpublished results. Consequently, these preliminary studies could provide the first demonstration that the TRH neurons directly regulated by leptin play a significant role in the DIO condition by allowing the HPT axis to continue to be functional when leptin resistance is established at the level of the ARC.

Although these preliminary data are compelling, these neurons also contain classical transmitters like GABA, glutamate and acetyl-choline that could influence TRH neurons even when the melanocortin receptors are not functional. Further studies are needed to demonstrate this possibility.

According to this idea, Halaas et al. Scarpace et al. Thus, it seems that the direct action of leptin on TRH neurons is one of the potential mechanisms to increase energy expenditure independently of the anorectic action coming from the ARC.

As described earlier in this review, thyroid hormones could also increase energy expenditure in DIO rats either directly, via up regulation of UCPs and basal body temperature, or indirectly via an increase in the sensitivity to the sympathetic activity [ ; ]. However, it is important to mention that changes in the activity of the autonomic system, independent of the HPT axis and leptin, may also contribute to increase the energy expenditure of DIO rats [ ].

Direct leptin action on TRH neurons may explain other side effects of obesity such as hypertension. It has been shown that diencephalic TRH mediates the central leptin-induced increase of blood pressure in rats [ ].

Moreover, Landa et al. These findings suggest that the selective leptin action on TRH neurons could contribute to the overall phenotype of obese individuals. In conclusion, the possibility of the existence of a group of hypothalamic TRH neurons sensitive to the leptin-induced increase of pSTAT3 signaling in obese animals is a novel aspect in the interaction between the HPT axis and leptin that may have important implications in the future development of anti-obesity drugs.

A recent study examined the effect of thyrotoxicosis and hypothyroidism on whole body energy metabolism and spontaneous physical activity in rats. Thyrotoxicosis showed to induce hyper-metabolism, increase food intake, and favoring lipid replenishment by increasing triglyceride derived fatty acid uptake in oxidative tissues.

This finding suggests that thyroid hormone might regulate fatty acid uptake from triglycerides rich lipoproteins in a tissue specific-manner [ ].

This current review is intended to describe the latest knowledge on the TRH neuron research by providing new insights into the cellular and molecular mechanisms controlling preproTRH gene expression, proTRH biosynthesis, the molecular determinants involved in the proper folding of the polypeptide, post-translational processing, and the differential sorting of the processing products to mature secretory granules Fig.

Since the discovery of the PCs in the late s a new frontier on the propeptide hormone biosynthesis and processing research has come to fruition. It is particularly relevant to emphasize the concept that secretion of any particular peptide or neuropeptide hormone depends on a series of post-translational modification carried out by a group of different processing enzymes located in a unique environment within the secretory system.

These enzymes, as we recently learned, are also regulated by important hormones involved thyroid physiology such as leptin and T 3 itself Figs.

It is also described to some extend the biological action of TRH in the thyroid axis during metabolic perturbations including cold stress, and the thyroid response in starvation and obesity. The recent view on this endocrine axis is that in order to maintain the homeostasis of the whole body metabolism and temperature it requires the participation of multiple factors coming from different brain nuclei, including the hypothalamus, and hormones from the periphery acting in a very coordinated and tightly regulated fashion.

Although there are other factors affecting the regulation of the hypophysiotropic TRH neurons, emphasis was placed in the review on those related to nutritional control of the HPT axis and cold stress Fig. At the hypothalamic level, evidence shows that fasting causes the increase of D2 in tanycytes promoting a conversion of T 4 to T 3 Fig. The information on human preproTRH expression is limited however, a recent study had showed that the participating proteins in the regulation of hypothalamic TRH during fasting in rodents are also expressed in the human hypothalamus [ ].

D2 is expressed in glial cells of the infundibular nucleus, which is the human homologue of the rat ARC [ ]. The physiological role of MCT8 was confirmed in mutations found in humans and mouse genetic models showing impairment in the regulation of preproTRH mRNA expression by thyroid hormone [ ; ; ; ].

Based on the new knowledge on the TRH neuron biology, it has been recently suggested to operate as a metabolic sensor since it is regulated at multiple levels to control thyroid function and metabolism [ ]. This illustration shows the multiple targets that leptin and T 3 have in regulating the output of TRH. Tanycytes incorporate T 4 and converted it to T 3 by D2, and together with T 3 coming from the periphery reach TRH neurons via specific transporters such as the monocarboxylate transporter MCT8 inhibiting gene expression by affecting the TRH promoter through binding to the THR b 2 isoform leading to the recruitment of cofactors such as SRC Post-translational processing of proTRH occurs during the transport of the prohormone in the axons reaching the median eminence.

The amount of TRH released from the axon terminals in the median eminence to the defenestrated capillaries can be controled by the degrading tanycyte-bound enzyme PPII, which is positively regulated by thyroid hormone. The potential effect of leptin via an activation of the sympathetic nervous system has been suggested, and in turn, increases the expression of BAT-UCP1 mRNA by the conversion of T4 to T3 facilitated by D2 increased activity. The thyroid gland uses iodine from food to make two thyroid hormones: triiodothyronine T3 and thyroxine T4.

It also stores these thyroid hormones and releases them as they are needed. The hypothalamus and the pituitary gland , which are located in the brain, help control the thyroid gland.

The hypothalamus releases thyrotropin-releasing hormone TRH , which stimulates the pituitary gland to release thyroid-stimulating hormone TSH. When the hypothalamus and pituitary are working normally, they sense when:. See a picture of thyroid hormone production. Author: Healthwise Staff. This information does not replace the advice of a doctor. Lactotroph cells in the pituitary gland produce prolactin , where it is stored and then released into the bloodstream.

The anterior pituitary hormones enter the systemic circulation and bind to their receptors on other target organs. In the case of TSH, the target organ is the thyroid gland. Clearly, robust control systems must be in place to prevent over or under-secretion of hypothalamic and anterior pituitary hormones. Where is thyrotropin releasing hormone released from? Category: medical health thyroid disorders. Thyrotropin - releasing hormone TRH , is a hypophysiotropic hormone , produced by neurons in the hypothalamus, that stimulates the release of thyroid-stimulating hormone TSH and prolactin from the anterior pituitary.

What stimulates GHRH release? GHRH is released from neurosecretory nerve terminals of these arcuate neurons, and is carried by the hypothalamo-hypophyseal portal system to the anterior pituitary gland, where it stimulates growth hormone GH secretion by stimulating the growth hormone- releasing hormone receptor.

What does TSH stand for? TSH stands for thyroid stimulating hormone. A TSH test is a blood test that measures this hormone. The thyroid is a small, butterfly-shaped gland located near your throat. Your thyroid makes hormones that regulate the way your body uses energy. What happens when TSH is released?

The hypothalamic-pituitary axis regulates TSH release. When T4 is released into circulation, it can be converted to T3 through the process of deiodination. Which area of the brain regulates the endocrine system? The hypothalamus is known as the master switchboard because it's the part of the brain that controls the endocrine system.

This situation is referred to as secondary or central hypothyroidism. About Contact Events News. Search Search. You and Your Hormones. Students Teachers Patients Browse. Human body. Home Hormones Thyrotropin-releasing hormone. Thyrotropin-releasing hormone Thyrotropin-releasing hormone is produced by the hypothalamus.

It plays an important role in the regulation of thyroid gland activity. Alternative names for thyrotropin-releasing hormone Thyrotrophin-releasing hormone; TRH What is thyrotropin-releasing hormone?