RESUMO

Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) is an intercellular signal produced mainly by neurons. Among the multiple pharmacological effects of TRH, that on food intake is not well understood. We review studies demonstrating that peripheral injection of TRH generally produces a transient anorexic effect, discuss the pathways that might initiate this effect, and explain its short half-life. In addition, central administration of TRH can produce anorexic or orexigenic effects, depending on the site of injection, that are likely due to interaction with TRH receptor 1. Anorexic effects are most notable when TRH is injected into the hypothalamus and the nucleus accumbens, while the orexigenic effect has only been detected by injection into the brain stem. Functional evidence points to TRH neurons that are prime candidate vectors for TRH action on food intake. These include the caudal raphe nuclei projecting to the dorsal motor nucleus of the vagus, and possibly TRH neurons from the tuberal lateral hypothalamus projecting to the tuberomammillary nuclei. For other TRH neurons, the anatomical or physiological context and impact of TRH in each synaptic domain are still poorly understood. The manipulation of TRH expression in well-defined neuron types will facilitate the discovery of its role in food intake control in each anatomical scene.

RESUMO

The dorsomedial nucleus of the hypothalamus (DMH) is part of the brain circuits that modulate organism responses to the circadian cycle, energy balance, and psychological stress. A large group of thyrotropin-releasing hormone (Trh) neurons is localized in the DMH; they comprise about one third of the DMH neurons that project to the lateral hypothalamus area (LH). We tested their response to various paradigms. In male Wistar rats, food restriction during adulthood, or chronic variable stress (CVS) during adolescence down-regulated adult DMH Trh mRNA levels compared to those in sedentary animals fed ad libitum; two weeks of voluntary wheel running during adulthood enhanced DMH Trh mRNA levels compared to pair-fed rats. Except for their magnitude, female responses to exercise were like those in male rats; in contrast, in female rats CVS did not change DMH Trh mRNA levels. A very strong negative correlation between DMH Trh mRNA levels and serum corticosterone concentration in rats of either sex was lost in CVS rats. CVS canceled the response to food restriction, but not that to exercise in either sex. TRH receptor 1 (Trhr) cells were numerous along the rostro-caudal extent of the medial LH. In either sex, fasting during adulthood reduced DMH Trh mRNA levels, and increased LH Trhr mRNA levels, suggesting fasting may inhibit the activity of TRHDMH->LH neurons. Thus, in Wistar rats DMH Trh mRNA levels are regulated by negative energy balance, exercise and chronic variable stress through sex-dependent and -independent pathways.

Assuntos

RESUMO

The hypothalamus-pituitary-thyroid-axis (HPT) is one of the main neuroendocrine axes that control energy expenditure. The activity of hypophysiotropic thyrotropin releasing hormone (TRH) neurons is modulated by nutritional status, energy demands and stress, all of which are sex dependent. Sex dimorphism has been associated with sex steroids whose concentration vary along the life-span, but also to sex chromosomes that define not only sexual characteristics but the expression of relevant genes. In this review we describe sex differences in basal HPT axis activity and in its response to stress and to metabolic challenges in experimental animals at different stages of development, as well as some of the limited information available on humans. Literature review was accomplished by searching in Pubmed under the following words: "sex dimorphic" or "sex differences" or "female" or "women" and "thyrotropin" or "thyroid hormones" or "deiodinases" and "energy homeostasis" or "stress". The most representative articles were discussed, and to reduce the number of references, selected reviews were cited.

Assuntos

RESUMO

Thyroid hormones (THs) are ancient signaling molecules that contribute to the regulation of metabolism, energy homeostasis and growth. In vertebrates, the hypothalamus-pituitary-thyroid (HPT) axis links the corresponding organs through hormonal signals, including thyrotropin releasing factor (TRF), and thyroid stimulating hormone (TSH) that ultimately activates the synthesis and secretion of THs from the thyroid gland. Although this axis is conserved among most vertebrates, the identity of the hypothalamic TRF that positively regulates TSH synthesis and secretion varies. We review the evolution of the hypothalamic factors that induce TSH secretion, including thyrotropin-releasing hormone (TRH), corticotrophin-releasing hormone (CRH), urotensin-1-3, and sauvagine, and non-mammalian glucagon-like peptide in metazoans. Each of these peptides is part of an extracellular communication unit likely composed of at least 3 elements: the peptide, G-protein coupled receptor and bioavailability regulator, set up on the central neuroendocrine articulation. The bioavailability regulators include a TRH-specific ecto-peptidase, pyroglutamyl peptidase II, and a CRH-binding protein, that together with peptide secretion/transport rate and transduction coupling and efficiency at receptor level shape TRF signal intensity and duration. These vertebrate TRF communication units were coopted from bilaterian ancestors. The bona fide elements appeared early in chordates, and are either used alternatively, in parallel, or sequentially, in different vertebrate classes to control centrally the activity of the HPT axis. Available data also suggest coincidence between apparition of ligand and bioavailability regulator.

Assuntos

RESUMO

Thyrotropin releasing hormone (TRH: Glp-His-Pro-NH2) is a peptide mainly produced by brain neurons. In mammals, hypophysiotropic TRH neurons of the paraventricular nucleus of the hypothalamus integrate metabolic information and drive the secretion of thyrotropin from the anterior pituitary, and thus the activity of the thyroid axis. Other hypothalamic or extrahypothalamic TRH neurons have less understood functions although pharmacological studies have shown that TRH has multiple central effects, such as promoting arousal, anorexia and anxiolysis, as well as controlling gastric, cardiac and respiratory autonomic functions. Two G-protein-coupled TRH receptors (TRH-R1 and TRH-R2) transduce TRH effects in some mammals although humans lack TRH-R2. TRH effects are of short duration, in part because the peptide is hydrolyzed in blood and extracellular space by a M1 family metallopeptidase, the TRH-degrading ectoenzyme (TRH-DE), also called pyroglutamyl peptidase II. TRH-DE is enriched in various brain regions but is also expressed in peripheral tissues including the anterior pituitary and the liver, which secretes a soluble form into blood. Among the M1 metallopeptidases, TRH-DE is the only member with a very narrow specificity; its best characterized biological substrate is TRH, making it a target for the specific manipulation of TRH activity. Two other substrates of TRH-DE, Glp-Phe-Pro-NH2 and Glp-Tyr-Pro-NH2, are also present in many tissues. Analogs of TRH resistant to hydrolysis by TRH-DE have prolonged central efficiency. Structure-activity studies allowed the identification of residues critical for activity and specificity. Research with specific inhibitors has confirmed that TRH-DE controls TRH actions. TRH-DE expression by ß2-tanycytes of the median eminence of the hypothalamus allows the control of TRH flux into the hypothalamus-pituitary portal vessels and may regulate serum thyrotropin secretion. In this review we describe the critical evidences that suggest that modification of TRH-DE activity in tanycytes, and/or in other brain regions, may generate beneficial consequences in some central and metabolic disorders and identify potential drawbacks and missing information needed to test these hypotheses.

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Starvation induces tertiary hypothyroidism in adult rodents. Response of the hypothalamus-pituitary-thyroid (HPT) axis to starvation is stronger in adult males than in females. To improve the description of this sexual dimorphism, we analyzed the dynamics of HPT axis response to fasting at multiple levels. In adult rats of the same cohort, 24 and 48 h of starvation inhibited paraventricular nucleus Trh expression and serum concentrations of TSH and T4 earlier in males than in females, with lower intensity in females than in males. In adult females fasted for 36-72 h, serum TSH concentration decreased after 36 h, when the activity of thyrotropin-releasing hormone (TRH)-degrading ectoenzyme was increased in the median eminence. The kinetics of these events were distinct from those previously observed in male rats. We suggest that the sex difference in TSH secretion kinetics is driven not only at the level of paraventricular nucleus TRH neurons, but also by differences in post-secretory catabolism of TRH, with enhancement of TRH-degrading activity more sustained in male than female animals.

Assuntos

RESUMO

The activity of the hypothalamus-pituitary-thyroid (HPT) axis is inhibited by energy deficit, by acute or chronic stress, but activated by cold exposure or exercise. Because stress curtails acute cold induced activation of HPT, we evaluated the effect of chronic stress on HPT axis response to voluntary exercise, a persistent energy-demanding situation. Adult male and female Wistar rats were exposed to restraint stress, 30 min/day for 2 weeks, or to isolation (Iso) [post-natal day [PND] 30-63]. Exercise was performed (7 p.m.-7 a.m.) in a running wheel, sedentary controls stayed in individual cages (Sed); at 7 a.m. they were housed with their cage mate or individually (Iso); food intake by the exercised group was measured day and night to pair-fed Sed. At sacrifice, hormones, mRNA levels and tissue weights were quantified. Control or restrained adult rats had access to running wheel daily for 2 weeks. Compared to C, exercise decreased white adipose tissue (WAT) mass in females and males, increased hypothalamic paraventricular nucleus (PVN)-Trh expression in males proportionally to exercise performed, and increased TSH and T4 serum concentration in females. These changes were not detected in restrained groups. Starting at PND 63 control (2/cage) and isolated (1/cage) rats either exercised on 10 alternated nights or were sedentary. In control male animals, compared to Sed rats, exercise did not decrease WAT mass, nor changed HPT axis activity, but increased Pomc and deiodinase 2 (Dio2) expression in mediobasal hypothalamus (MBH), adrenergic receptor ß3 and uncoupling protein-1 in brown adipose tissue. In control female animals, exercise decreased WAT mass, increased Pomc, Dio2, and Trhde expression in MBH, and TSH serum concentration. Iso females had lower TSH and T4 serum concentration, Dio2 and Trhde expression in MBH than controls. The stress response was higher in isolated males than females, but in males it did not alter the effects of exercise, in contrast to isolated females that had a blunted response to exercise compared to controls. In conclusion, chronic stress interferes with metabolic effects produced by exercise, such as loss of WAT mass, coincident with dampening of HPT activity.

RESUMO

Central and peripheral mechanisms that modulate energy intake, partition and expenditure determine energy homeostasis. Thyroid hormones (TH) regulate energy expenditure through the control of basal metabolic rate and thermogenesis; they also modulate food intake. TH concentrations are regulated by the hypothalamus-pituitary-thyroid (HPT) axis, and by transport and metabolism in blood and target tissues. In mammals, hypophysiotropic thyrotropin-releasing hormone (TRH) neurons of the paraventricular nucleus of the hypothalamus integrate energy-related information. They project to the external zone of the median eminence (ME), a brain circumventricular organ rich in neuron terminal varicosities and buttons, tanycytes, other glial cells and capillaries. These capillary vessels form a portal system that links the base of the hypothalamus with the anterior pituitary. Tanycytes of the medio-basal hypothalamus express a repertoire of proteins involved in transport, sensing, and metabolism of TH; among them is type 2 deiodinase, a source of 3,3',5-triiodo-L-thyronine necessary for negative feedback on TRH neurons. Tanycytes subtypes are distinguished by position and phenotype. The end-feet of ß2-tanycytes intermingle with TRH varicosities and terminals in the external layer of the ME and terminate close to the ME capillaries. Besides type 2 deiodinase, ß2-tanycytes express the TRH-degrading ectoenzyme (TRH-DE); this enzyme likely controls the amount of TRH entering portal vessels. TRH-DE is rapidly upregulated by TH, contributing to TH negative feedback on HPT axis. Alterations in energy balance also regulate the expression and activity of TRH-DE in the ME, making ß2-tanycytes a hub for energy-related regulation of HPT axis activity. ß2-tanycytes also express TRH-R1, which mediates positive effects of TRH on TRH-DE activity and the size of ß2-tanycyte end-feet contacts with the basal lamina adjacent to ME capillaries. These end-feet associations with ME capillaries, and TRH-DE activity, appear to coordinately control HPT axis activity. Thus, down-stream of neuronal control of TRH release by action potentials arrival in the external layer of the median eminence, imbricated intercellular processes may coordinate the flux of TRH into the portal capillaries. In conclusion, ß2-tanycytes appear as a critical cellular element for the somatic and post-secretory control of TRH flux into portal vessels, and HPT axis regulation in mammals.

RESUMO

Neonatal stress contributes to the development of obesity and has long-lasting effects on elements of the hypothalamus-pituitary-thyroid (HPT) axis. Given the importance of thyroid hormones in metabolic regulation, we studied the effects of maternal separation and a high-fat/high-carbohydrate diet (HFC), offered from puberty or adulthood, on HPT axis activity of adult male and female Wistar rats. Pups were non-handled (NH) or maternally separated (MS) 3 h/day at postnatal days (Pd) 2-21. In a first experiment, at Pd60, rats had access to chow or an HFC diet (cookies, peanuts, chow) for 1 month. Male and female NH and MS rats that consumed the HFC diet increased their caloric intake, body weight, and serum insulin levels; fat weight increased in all groups except in MS males, and serum leptin concentration increased only in females. Mediobasal hypothalamus (MBH) Pomc expression increased in NH-HFC females and Npy decreased in NH-HFC males. MS males showed insulinemia and hypercortisolemia that was attenuated by the HFC diet. The HPT axis activity response to an HFC diet was sex-specific; expression of MBH thyrotropin-releasing hormone-degrading ectoenzyme (Trhde) increased in NH and MS males; serum TSH concentration decreased in NH males, and T4 increased in NH females. In a second experiment, rats were fed chow or an HFC diet from Pd30 or 60 until Pd160 and exposed to 1 h restraint before sacrifice. Regardless of neonatal stress, age of diet exposition, or sex, the HFC diet increased body and fat weight and serum leptin concentration; it induced insulinemia in males, but in females only in Pd30 rats. The HFC diet's capacity to curtail the hypothalamus-pituitary-adrenal axis response to restraint was impaired in MS males. In restrained rats, expression of Trh in the paraventricular nucleus of the hypothalamus, Dio2 and Trhde in MBH, and serum thyroid hormone concentration were altered differently depending on sex, age of diet exposition, and neonatal stress. In conclusion, metabolic alterations associated to an HFC-diet-induced obesity are affected by sex or time of exposition, while various parameters of the HPT axis activity are additionally altered by MS, pointing to the complex interplay that these developmental influences exert on HPT axis activity in adult rats.

RESUMO

AIMS: Voltage-gated potassium channels 1.3 (Kv1.3) can be targeted to reduce diet-induced obesity and insulin resistance in mice. Since species-specific differences in Kv1.3 expression and pharmacology have been observed, we tested the effect of Vm24, a high-affinity specific blocker of Kv1.3 channels from Vaejovis mexicanus smithi, on body weight (BW), glucose tolerance and insulin resistance in diet-induced obese rats. MATERIALS AND METHODS: Young adult male Wistar rats were switched to a high-fat/high-fructose (HFF) diet. Eighteen days later animals were divided in two groups: vehicle and Vm24 group. Subcutaneous injections were applied every other day until sacrifice 2months later. An additional cohort was maintained on standard chow. KEY FINDINGS: The HFF diet promoted obesity. Treatment with Vm24 did not alter various metabolic parameters such as food intake, BW gain, visceral white adipose tissue mass, adipocyte diameter, serum glucose, leptin and thyroid hormone concentrations, brown adipose tissue mass or uncoupling protein-1 expression, and insulin tolerance. Vm24 did reduce basal and glucose-stimulated serum insulin concentrations, serum C-peptide concentration, increased QUICKI, and tended to lower HOMA-IR. Vm24 treatment did not change the activation of insulin receptor substrate-1, but enhanced protein-kinase B activation and membrane glucose-transporter 4 (GLUT4) protein levels in skeletal muscle. SIGNIFICANCE: In conclusion, in male rats, long-term blockade of Kv1.3 channels with Vm24 does not reduce weight gain and visceral adiposity induced by HFF diet; instead, it reduces serum insulin concentration, and enhances GLUT4 mobilization in skeletal muscle.

Assuntos