Thyrotropin-releasing Hormone Research Articles

Growth hormone increase by luteinizing hormone-releasing hormone reflects gonadotroph-related characteristics in acromegaly.

We previously showed the clinical characteristics of acromegaly with a paradoxical growth hormone (GH) response to oral glucose or thyrotropin-releasing hormone. However, the clinical characteristics of acromegaly with an increased GH response to luteinizing hormone-releasing hormone (LHRH responders) remain unclear. The aim of the present study was to evaluate the clinical characteristics, especially gonadotroph-related characteristics of LHRH responders in acromegaly. The clinical characteristics of 33 LHRH responders and 81 LHRH nonresponders were compared. No differences in age, sex or basal serum levels of GH, insulin-like growth factor-1 (IGF-1), and gonadotropin were observed between the two groups. Steroidogenic factor 1 (SF-1), gonadotropin-releasing hormone receptor (GnRHR), and LH expression was more frequently observed in LHRH responders (P < 0.05). In addition, a greater increased rate of GH after LHRH loading, and the proportion of GnRHR and gonadotropin expression was observed in pituitary tumor with SF-1 expression than that without the expression (P < 0.01). LHRH responders showed a greater GH decrease in the octreotide test and a greater IGF-1 decrease after first-generation somatostatin ligand than LHRH nonresponders (P < 0.05). Furthermore, the proportion of hypointense pituitary tumors on T2-weighted magnetic resonance imaging and tumors with densely granulated type was higher in LHRH responders than in LHRH nonresponders, respectively (P < 0.05). No difference between the two groups was observed in either somatostatin receptor 2 or 5 expression. The increased GH response to LHRH is associated with the gonadotroph-related characteristics. This response may reflect the biological characteristics of somatotroph tumors.

Thyrotropin-Releasing Hormone and Food Intake in Mammals: An Update.

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.

Hypopituitarism with secondary adrenocortical insufficiency and arginine vasopressin deficiency due to hypophysitis after COVID-19 vaccination: a case report

BackgroundAlthough vaccination against coronavirus disease (COVID-19) has several side effects, hypopituitarism due to hypophysitis has rarely been reported.Case presentationAn 83-year-old healthy woman, who had received her fourth COVID-19 vaccine dose 2 days before admission, presented to the emergency department with difficulty moving. On examination, impaired consciousness (Glasgow Coma Scale: 14) and fever were observed. Computed tomography and magnetic resonance imaging of the head revealed swelling from the sella turcica to the suprasellar region. Her morning serum cortisol level was low (4.4 μg/dL) and adrenocorticotropic hormone level was normal (21.6 pg/mL). Central hypothyroidism was also suspected (thyroid stimulating hormone, 0.46 μIU/mL; free triiodothyronine, 1.86 pg/mL; free thyroxine, 0.48 ng/dL). Secondary adrenocortical insufficiency, growth hormone deficiency, delayed gonadotropin response, and elevated prolactin levels were also observed. After administration of prednisolone and levothyroxine, her consciousness recovered. On the 7th day of admission, the patient developed polyuria, and arginine vasopressin deficiency was diagnosed using a hypertonic saline test. On the 15th day, the posterior pituitary gland showed a loss of high signal intensity and the polyuria resolved spontaneously. On the 134th day, the corticotropin-releasing hormone loading test showed a normal response; however, the thyrotropin-releasing hormone stimulation test showed a low response. The patient’s disease course was stable with continued thyroid and adrenal corticosteroid supplementation.ConclusionsHerein, we report a rare case of anterior hypopituitarism and arginine vasopressin deficiency secondary to hypophysitis following COVID-19 vaccination.

Evaluating the TRH Test: Prolactin Cutoff Level on the Prevalence of Reactive Hyperprolactinemia Among PCOS Women [ID 2683598

INTRODUCTION: The prolactin cutoff value is currently under discussion, although accepted values range between 15 and 25 ng/mL. The thyrotropin-releasing hormone (TRH) test is a validated methodology for the study of reactive hyperprolactinemia, but there is no consensus for which group of patients it should be used, especially in those women diagnosed with polycystic ovary syndrome (PCOS). The objective of this study was to classify the prolactin values obtained from the TRH test in women of reproductive age but previously diagnosed with PCOS, according to ranges: group A: PRL, less than 15 ng/mL; group B: PRL, 15–20 ng/mL; and group C: PRL, 20–25 ng/mL. METHODS: Three hundred seventy-eight women between 12 and 40 years old, previously diagnosed with PCOS according to Rotterdam criteria, and without a diagnosis of hyperprolactinemia or use of antipsychotics were considered. An initial prolactin measurement was performed, the TRH test was performed after 15 and 30 minutes, and the resulting values were classified in groups A, B, and C, respectively. RESULTS: The number of patients obtained was 266. Group A (n=199) had 34.17% (68) of patients with an altered TRH test, whereas in group B (n=42) 47.62% (20) had an abnormality in the test. Finally, in group C (n=25), 28.00% (7) showed an altered TRH test. CONCLUSION: Group B is the one with the highest prevalence of reactive hyperprolactinemia compared to groups A and C. It is concluded that the application of the TRH test is suggested in those patients with PCOS with prolactin ranges between 15 and 20 ng/mL.

Clinical Characteristics, Diagnosis, and Treatment of Thyroid Stimulating Hormone-Secreting Pituitary Neuroendocrine Tumor (TSH PitNET): A Single-Center Experience.

Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of PitNET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

Valproate decreases transgenerationally blood pressure by affecting thyrotropin-releasing hormone promoter DNA methylation and gene expression in spontaneously hypertensive rat

Valproate decreases transgenerationally blood pressure by affecting thyrotropin-releasing hormone promoter DNA methylation and gene expression in spontaneously hypertensive rat

Characterization of thyrotropin-releasing hormone producing neurons in sea urchin, from larva to juvenile.

Most sea urchin species are indirect developers, going through a larval stage called pluteus. The pluteus possesses its own nervous system, consisting mainly of the apical organ neurons (controlling metamorphosis and settlement) and ciliary band neurons (controlling swimming behavior and food collection). Additional neurons are located in various areas of the gut. In recent years, the molecular complexity of this apparently "simple" nervous system has become apparent, with at least 12 neuronal populations identified through scRNA-sequencing in the species Strongylocentrotus purpuratus. Among these, there is a cluster of neurosecretory cells that produce a thyrotropin-releasing hormone-type neuropeptide (TRHergic) and that are also photosensory (expressing a Go-Opsin). However, much less is known about the organization of the nervous system in other sea urchin species. The aim of this work was to thoroughly characterize the localization of the TRHergic cells from early pluteus to juvenile stages in the Mediterranean sea urchin species Paracentrotus lividus combining immunostaining and whole mount in situ hybridization. We also compared the localization of TRHergic cells in early plutei of two other sea urchin species, Arbacia lixula and Heliocidaris tuberculata. This work provides new information on the anatomy and development of the nervous system in sea urchins. Moreover, by comparing the molecular signature of the TRHergic cells in P. lividus and S. purpuratus, we have obtained new insights how TRH-type neuropeptide signaling evolved in relatively closely related species.

A challenging case of a pituitary macroadenoma and toxic thyroid adenoma with inappropriate TSH secretion.

Thyroid-stimulating hormone-secreting pituitary adenomas (TSHomas) are rare, accounting for less than 1% of all pituitary adenomas. We present a case of hyperthyroidism secondary to a likely TSHoma and coexisting functional thyroid adenoma. Laboratory errors and familial abnormalities in thyroid function tests were ruled out, and a diagnosis of the toxic thyroid adenoma was confirmed on a thyroid uptake scan. However, the triiodothyronine suppression test was contraindicated due to the patient's cardiovascular disease, and the thyrotropin-releasing hormone stimulation test, measurement of glycoprotein hormone alpha-subunit, and genetic testing were unavailable. Magnetic resonance imaging of the brain revealed a suprasellar pituitary macroadenoma measuring 40 mm × 20.3 mm × 17 mm. The patient was initiated on carbimazole; however, thyroid stimulating hormone and thyroxine levels remained elevated. The patient declined trans-sphenoidal surgery and was treated with radioactive iodine to manage the toxic thyroid adenoma, leading to reduced thyroxine levels and symptom improvement. Unfortunately, the patient passed away before long-acting somatostatin analogs became available. This case highlights the diagnostic and therapeutic challenges involved in managing thyrotoxicosis with dual etiology. Hyperthyroidism can have multiple etiologies, which can coexist in the same patient. Persistent discordant thyroid function tests warrant further investigation. The gold standard for diagnosis of TSHomas remains immunohistochemical analysis of the tumor tissue.

Roxadustat and transfusional iron overload induced hypothyroidism in a hemodialysis patient: a case report with a literature review

BackgroundAlthough roxadustat has been reported to cause central hypothyroidism, the details of the mechanisms and clinical characteristics of patients who are prone to developing hypothyroidism with roxadustat are uncertain.Case presentationA 53-year-old man with a 3-year history of hemodialysis due to diabetic kidney disease who had been treated with roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, for 2 years was admitted to the hospital because of worsening gait disturbance and impaired consciousness. He had also acquired pure red cell aplasia associated with T-cell large granular lymphocytic leukemia and received multiple blood transfusions. Because his serum concentration of thyroid hormones was low, we diagnosed him with hypothyroidism, and his consciousness level recovered to normal with thyroid hormone replacement therapy. Computed tomography revealed a high-intensity atrophic thyroid gland, and magnetic resonance imaging showed diffusely reduced T2 and T1 signals of the pituitary anterior gland. These findings confirmed the accumulation of iron in the pituitary and thyroid glands. Combined pituitary stimulation tests with thyrotropin-releasing hormone, luteinizing hormone-releasing hormone, and corticotropin-releasing hormone revealed that the patient had pan-hypopituitarism. After discontinuation of roxadustat, the patient was treated with another hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat. One month after switching medication, a stimulation test with thyrotropin-releasing hormone showed normal responses to thyroid-stimulating hormone. The patient was treated with levothyroxine 50 μg daily without any significant symptoms and is currently under follow-up observation as an outpatient.ConclusionsWe encountered a dialysis patient with roxadustat-induced hypothyroidism associated with transfusion iron overload. To our knowledge, this is the first case to clearly show that roxadustat can impair thyroid-stimulating hormone secretion in repeated thyrotropin-releasing hormone stimulation tests. Because the present patient had received roxadustat for more than 2 years before hypothyroidism became apparent, regular monitoring of the thyroid function may be needed in patients with renal anemia who have been treated with roxadustat, especially those at high risk of thyroid dysfunction.

Influence of the gut microbiome on appetite-regulating neuropeptides in the hypothalamus: Insight from conventional, antibiotic-treated, and germ-free mouse models of anorexia nervosa

Recent research highlights the profound impact of the gut microbiome on neuropsychiatric disorders, shedding light on its potential role in shaping human behavior. In this study, we investigate the role of the gut microbiome in appetite regulation using activity-based anorexia (ABA) mouse model of anorexia nervosa (AN) — a severe eating disorder with significant health consequences. ABA was induced in conventional, antibiotic-treated, and germ-free mice. Our results show the clear influence of the gut microbiome on the expression of four orexigenic (neuropeptide Y, agouti-related peptide, melanin-concentrating hormone, and orexin) and four anorexigenic peptides (cocaine- and amphetamine-regulated transcript, corticotropin-releasing hormone, thyrotropin-releasing hormone, and pro-opiomelanocortin) in the hypothalamus. Additionally, we assessed alterations in gut barrier permeability. While variations were noted in germ-free mice based on feeding and activity, they were not directly attributable to the gut microbiome. This research emphasizes that the gut microbiome is a pivotal factor in AN's appetite regulation beyond just dietary habits or physical activity.

Intracerebroventricular administration of TRH Agonist, RX-77368 alleviates visceral pain induced by colorectal distension in rats

Thyrotropin-releasing hormone (TRH) acts centrally to exert pleiotropic actions independently from its endocrine function, including antinociceptive effects against somatic pain in rodents. Whether exogenous or endogenous activation of TRH signaling in the brain modulates visceral pain is unknown. Adult male Sprague-Dawley rats received an intracerebroventricular (ICV) injection of the stable TRH analog, RX-77368 (10, 30 and 100 ng/rat) or saline (5 µl) or were semi-restrained and exposed to cold (4°C) for 45 min. The visceromotor response (VMR) to graded phasic colorectal distensions (CRD) was monitored using non-invasive intracolonic pressure manometry. Naloxone (1 mg/kg) was injected subcutaneously 10 min before ICV RX-77368 or saline. Fecal pellet output was monitored for 1 h after ICV injection. RX-77368 ICV (10, 30 and 100 ng/rat) reduced significantly the VMR by 56.7%, 67.1% and 81.1% at 40 mmHg and by 30.3%, 58.9% and 87.4% at 60 mmHg respectively vs ICV saline. Naloxone reduced RX-77368 (30 and 100 ng, ICV) analgesic response by 51% and 28% at 40 mmHg and by 30% and 33% at 60 mmHg respectively, but had no effect per se. The visceral analgesia was mimicked by the acute exposure to cold. At the doses of 30 and 100 ng, ICV RX-77368 induced defecation within 30 min. These data established the antinociceptive action of RX-77368 injected ICV in a model of visceral pain induced by colonic distension through recruitment of both opioid and non-opioid dependent mechanisms.

Cerebral Artery Overexpression of the NMUR1 Gene Is Associated with Moyamoya Disease: A Weighted Gene Co-Expression Network Analysis

Introduction: This study aimed to elucidate mechanisms underlying moyamoya disease (MMD) pathogenesis and to identify potential novel biomarkers. We utilized gene co-expression networks to identify hub genes associated with the disease. Methods: Twenty-one middle cerebral artery (MCA) samples from MMD patients and 11 MCA control samples were obtained from the Gene Expression Omnibus (GEO) dataset, GSE189993. To discover functional pathways and potential biomarkers, weighted gene co-expression network analysis (WGCNA) was employed. The hub genes identified were re-assessed through differential gene expression analysis (DGEA) via DESeq2 for further reliability verification. Additional 4 samples from the superficial temporal arteries (STAs) from MMD patients were obtained from GSE141025, and a subgroup analysis stratified by arterial type (MCA vs. STA) DGEA was performed to assess if the hub genes associated with MMD are expressed significantly greater on the affected arteries compared to healthy ones in MMD. Results: WGCNA revealed a predominant module encompassing 139 hub genes, predominantly associated with the neuroactive ligand-receptor interaction (NLRI) pathway. Of those, 17 genes were validated as significantly differentially expressed. Neuromedin U receptor 1 (NMUR1) and thyrotropin-releasing hormone were 2 out of the 17 hub genes involved in the NLRI pathway (log fold change [logFC]: 1.150, p = 0.00028; logFC: 1.146, p = 0.00115, respectively). MMD-only subgroup analysis stratified by location showed that NMUR1 is significantly overexpressed in the MCA compared to the STA (logFC: 1.962; p = 0.00053) which further suggests its possible localized involvement in the progressive stenosis seen in the cerebral arteries in MMD. Conclusion: This is the first study to have performed WGCNA on samples directly affected by MMD. NMUR1 expression is well known to induce localized arterial smooth muscle constriction and, recently, type 2 inflammation which can predispose to arterial stenosis potentially advancing the symptoms and progression of MMD. Further validation and functional studies are necessary to understand the precise role of NMUR1 upregulation in MMD and its potential implications.

Linkage and association of rs3110045 and rs28499085 variants in the thyrotropin-releasing hormone receptor (TRHR) gene with the risk of familial type 2 diabetes

Type 2 diabetes (T2D) is a chronic and prevalent multisystemic disease that significantly increases morbidity and mortality. Dysfunction of the thyroid hormone system is common in patients with T2D, increasing their risk of both hyperthyroidism and hypothyroidism. Several components of the thyroid system are candidate risk genes for T2D. The thyrotropin-releasing hormone receptor (TRHR) gene encoding for TRHR is of particular interest since it is expressed by the dorsomedial hypothalamus neurons, which are known to regulate food intake. In humans, a variant in the TRHR gene has been previously reported in T2D patients in a population-based case-control study but not in familial T2D. We recruited 212 multigenerational families with T2D originated from the Italian peninsula with multiple cases of T2D and tested, via Pseudomarker 9 single nucleotide polymorphisms (SNPs) in the TRHR gene for linkage and linkage disequilibrium (i.e., linkage plus association) to/with T2D. We identified 2 novel risk variants (rs3110045 and rs28499085) significantly linked to and associated with the risk of T2D in the Italian families across several inheritance models. Our study is the first to confirm the previously reported association of TRHR gene with T2D and extends the risk to familial inheritance. However, functional and replication studies are still needed to confirm these results.

Neuropeptides and Their Roles in the Cerebellum.

Although more than 30 different types of neuropeptides have been identified in various cell types and circuits of the cerebellum, their unique functions in the cerebellum remain poorly understood. Given the nature of their diffuse distribution, peptidergic systems are generally assumed to exert a modulatory effect on the cerebellum via adaptively tuning neuronal excitability, synaptic transmission, and synaptic plasticity within cerebellar circuits. Moreover, cerebellar neuropeptides have also been revealed to be involved in the neurogenetic and developmental regulation of the developing cerebellum, including survival, migration, differentiation, and maturation of the Purkinje cells and granule cells in the cerebellar cortex. On the other hand, cerebellar neuropeptides hold a critical position in the pathophysiology and pathogenesis of many cerebellar-related motor and psychiatric disorders, such as cerebellar ataxias and autism. Over the past two decades, a growing body of evidence has indicated neuropeptides as potential therapeutic targets to ameliorate these diseases effectively. Therefore, this review focuses on eight cerebellar neuropeptides that have attracted more attention in recent years and have significant potential for clinical application associated with neurodegenerative and/or neuropsychiatric disorders, including brain-derived neurotrophic factor, corticotropin-releasing factor, angiotensin II, neuropeptide Y, orexin, thyrotropin-releasing hormone, oxytocin, and secretin, which may provide novel insights and a framework for our understanding of cerebellar-related disorders and have implications for novel treatments targeting neuropeptide systems.

Metabolic and Endocrine Insights in Donkeys.

Donkey medicine is gaining attention due to their increased use as companion animals, in shows, asinotherapy, etc. The increasing demand and unique aspects call for specialized care, requiring new information (physiology, infectious disorders, pharmacology, etc.). Since obesity is common in this species, hyperlipemia, metabolic syndrome and insulin dysregulation (ID) are common disorders in donkeys, in some cases with high mortality, either directly (multiorgan dysfunction) or indirectly due to poor quality of life (chronic laminitis). Donkeys have long-life expectancy and are often afflicted with pituitary pars intermedia dysfunction (PPID), a neurodegenerative and endocrine disease. Hyperlipemia is diagnosed based on high plasma triglyceride concentration in association with clinical findings and laboratory abnormalities from affected tissues (liver, kidney and pancreas). The measurement of resting serum insulin and plasma ACTH concentrations is the first step in ID and PPID diagnosis. In donkeys with clinical signs of ID (obesity or recurrent laminitis) or PPID (hypertrichosis, regional adiposity, laminitis and weight loss), where these hormones are in the normal or non-diagnostic range (donkey-specific cut-off values and reference ranges need to be established), dynamic tests are recommended (oral sugar test or thyrotropin-releasing hormone, respectively). Equine treatment protocols apply to donkeys, although pharmacological studies for most drugs, except pergolide, are lacking.

Clinical Characteristics, Diagnosis, and Treatment of Thyroid Stimulating Hormone-Secreting Pituitary Neuroendocrine Tumor (TSH PitNET): A Single-Center Experience.

Thyroid-stimulating hormone (TSH)-secreting pituitary neuroendocrine tumor (TSH PitNET) is a rare subtype of Pit- NET. We investigated the comprehensive characteristics and outcomes of TSH PitNET cases from a single medical center. Also, we compared diagnostic methods to determine which showed superior sensitivity. A total of 17 patients diagnosed with TSH PitNET after surgery between 2002 and 2022 in Samsung Medical Center was retrospectively reviewed. Data on comprehensive characteristics and treatment outcomes were collected. The sensitivities of diagnostic methods were compared. Seven were male (41%), and the median age at diagnosis was 42 years (range, 21 to 65); the median follow-up duration was 37.4 months. The most common (59%) initial presentation was hyperthyroidism-related symptoms. Hormonal co-secretion was present in four (23%) patients. Elevated serum alpha-subunit (α-SU) showed the greatest diagnostic sensitivity (91%), followed by blunted response at thyrotropin-releasing hormone (TRH) stimulation (80%) and elevated sex hormone binding globulin (63%). Fourteen (82%) patients had macroadenoma, and a specimen of one patient with heavy calcification was negative for TSH. Among 15 patients who were followed up for more than 6 months, 10 (67%) achieved hormonal and structural remission within 6 months postoperatively. A case of growth hormone (GH)/TSH/prolactin (PRL) co-secreting mixed gangliocytoma-pituitary adenoma (MGPA) was discovered. The majority of the TSH PitNET cases was macroadenoma, and 23% showed hormone co-secretion. A rare case of GH/TSH/PRL co-secreting MGPA was discovered. Serum α-SU and TRH stimulation tests showed great diagnostic sensitivity. Careful consideration is needed in diagnosing TSH PitNET. Achieving remission requires complete tumor resection. In case of nonremission, radiotherapy or medical therapy can improve the long-term remission rate.

The hypothalamic-pituitary-thyroid axis is intact in male insulin receptor substrate 4 knockout mice.

Loss of function mutations in the insulin receptor substrate 4 (IRS4) gene cause a rare form of X-linked congenital central hypothyroidism in boys and men. Affected individuals show decreased thyroid-stimulation hormone (TSH) secretion. Members of the IRS family canonically act as scaffold proteins between tyrosine kinase receptors and downstream effectors. How loss of IRS4 affects TSH synthesis or secretion is unresolved. We therefore assessed IRS4's role in the hypothalamic-pituitary-thyroid axis of Irs4 knockout mice. We generated two global Irs4 knockout mouse lines harboring either two or four base-pair deletions that result in frameshifts and loss of most of the IRS4 protein. Under normal laboratory conditions, Irs4 knockout males did not exhibit impairments in pituitary expression of TSH subunit genes (Tshb or Cga) or in the thyrotropin-releasing hormone (TRH) receptor. Additionally, their serum thyroid hormone, T3 (triiodothyronine) and T4 (thyroxine), and hypothalamic Trh expression levels were normal. When Irs4 knockouts were rendered hypothyroid with a low-iodine diet supplemented with propylthiouracil (PTU) for 3 weeks, their serum TSH increased similarly to wild-type males. Overall, Irs4 knockout mice do not exhibit central hypothyroidism or otherwise appear to phenocopy IRS4 deficient patients. Compensation by another IRS protein may explain euthyroidism in these animals.

GLP-1 Receptor Signaling Has Different Effects on the Perikarya and Axons of the Hypophysiotropic Thyrotropin-Releasing Hormone Synthesizing Neurons in Male Mice.

Background: Glucagon-like peptide 1 (GLP-1) is involved in the regulation of energy and glucose homeostasis. As GLP-1 has similar effects on the energy homeostasis as the hypophysiotropic thyrotropin-releasing hormone (TRH) neurons that regulate the hypothalamic-pituitary-thyroid (HPT) axis, we raised the possibility that the TRH neurons are involved in the mediation of the effects of GLP-1. Therefore, the relationship and interaction of the GLP-1 system and the TRH neurons of the hypothalamic paraventricular nucleus (PVN) were studied. Methods: To examine the anatomical and functional relationship of TRH neurons and the GLP-1 system in the PVN, immunocytochemistry, in situ hybridization, in vitro patch-clamp electrophysiology, metabolic phenotyping, and explant experiments were performed. Results: Our data demonstrate that the TRH neurons of the PVN are innervated by GLP-1 producing neurons and express the GLP-1 receptor (GLP-1R). However, not only do the GLP-1-innervated TRH neurons express GLP-1R but the receptor is also present in the axons of the hypophysiotropic TRH neurons in the blood-brain barrier free median eminence (ME) suggesting that peripherally derived GLP-1 may also influence the TRH neurons. In vitro, GLP-1 increased the firing rate of TRH neurons and depolarized them. In addition, GLP-1 directly stimulated the GABAergic input of a population of TRH neurons. Furthermore, GLP-1 inhibited the release of TRH from the hypophysiotropic axons in the ME. In vivo, peripheral GLP-1R agonist administration markedly inhibited the food intake and the energy expenditure, but had no effect on the TRH expression in the PVN and resulted in lower circulating free T4 levels. Conclusions: Our results indicate that GLP-1R activation has a direct stimulatory effect on TRH neurons in the PVN, but the activation of GLP-1R may also inhibit TRH neurons by facilitating their inhibitory inputs or by inhibiting the axon terminals of these cells in the ME. The innervation of TRH neurons by GLP-1 neurons suggests that TRH neurons might be influenced by both circulating GLP-1 and by GLP-1 neurons of the nucleus tractus solitarii. The lack of GLP-1R agonist-induced regulation of TRH neurons in vivo suggests that the HPT axis does not mediate the GLP-1R agonist-induced weight loss.

Palmitoylation of PKCδ by ZDHHC5 in hypothalamic microglia presents as a therapeutic target for fatty liver disease.

The hypothalamus plays a fundamental role in controlling lipid metabolism through neuroendocrine signals. However, there are currently no available drug targets in the hypothalamus that can effectively improve human lipid metabolism. In this study, we found that the antimalarial drug artemether (ART) significantly improved lipid metabolism by specifically inhibiting microglial activation in the hypothalamus of high-fat diet-induced mice. Mechanically, ART protects the thyrotropin-releasing hormone (TRH) neurons surrounding microglial cells from inflammatory damage and promotes the release of TRH into the peripheral circulation. As a result, TRH stimulates the synthesis of thyroid hormone (TH), leading to a significant improvement in hepatic lipid disorders. Subsequently, we employed a biotin-labeled ART chemical probe to identify the direct cellular target in microglial cells as protein kinase Cδ (PKCδ). Importantly, ART directly targeted PKCδ to inhibit its palmitoylation modification by blocking the binding of zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5), which resulted in the inhibition of downstream neuroinflammation signaling. In vivo, hypothalamic microglia-specific PKCδ knockdown markedly impaired ART-dependent neuroendocrine regulation and lipid metabolism improvement in mice. Furthermore, single-cell transcriptomics analysis in human brain tissues revealed that the level of PKCδ in microglia positively correlated with individuals who had hyperlipemia, thereby highlighting a clinical translational value. Collectively, these data suggest that the palmitoylation of microglial PKCδ in the hypothalamus plays a role in modulating peripheral lipid metabolism through hypothalamus-liver communication, and provides a promising therapeutic target for fatty liver diseases.

Receptor modulators associated with the hypothalamus -pituitary-thyroid axis.

The hypothalamus-pituitary-thyroid (HPT) axis maintains normal metabolic balance and homeostasis in the human body through positive and negative feedback regulation. Its main regulatory mode is the secretion of thyrotropin (TSH), thyroid hormones (TH), and thyrotropin-releasing hormone (TRH). By binding to their corresponding receptors, they are involved in the development and progression of several systemic diseases, including digestive, cardiovascular, and central nervous system diseases. The HPT axis-related receptors include thyrotropin receptor (TSHR), thyroid hormone receptor (TR), and thyrotropin-releasing hormone receptor (TRHR). Recently, research on regulators has become popular in the field of biology. Several HPT axis-related receptor modulators have been used for clinical treatment. This study reviews the developments and recent findings on HPT axis-related receptor modulators. This will provide a theoretical basis for the development and utilisation of new modulators of the HPT axis receptors.