TY - JOUR AU - Ruska, Yvette Magdolna AU - Péterfi, Zoltán Attila AU - Stiftné Szilvásy-Szabó, Anett AU - Kővári, Dóra AU - Hrabovszky, Erik AU - Dorogházi, Beáta Vanessza AU - Gereben, Balázs AU - Tóth, Blanka AU - Matziari, Magdalini AU - Wittmann, Gábor AU - Fekete, Csaba TI - GLP-1 Receptor Signaling Has Different Effects on the Perikarya and Axons of the Hypophysiotropic Thyrotropin-Releasing Hormone Synthesizing Neurons in Male Mice JF - THYROID J2 - THYROID VL - 34 PY - 2024 IS - 2 SP - 252 EP - 260 PG - 9 SN - 1050-7256 DO - 10.1089/thy.2023.0284 UR - https://m2.mtmt.hu/api/publication/34578220 ID - 34578220 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Batistuzzo, Alice AU - Salas-Lucia, Federico AU - Gereben, Balázs AU - Ribeiro, Miriam O AU - Bianco, Antonio C TI - Sustained Pituitary T3 Production Explains the T4-mediated TSH Feedback Mechanism JF - ENDOCRINOLOGY J2 - ENDOCRINOLOGY VL - 164 PY - 2023 IS - 12 PG - 9 SN - 0013-7227 DO - 10.1210/endocr/bqad155 UR - https://m2.mtmt.hu/api/publication/34391689 ID - 34391689 AB - The regulation of thyroid activity and thyroid hormone (TH) secretion is based on feedback mechanisms that involve the anterior pituitary TSH and medial basal hypothalamus TSH-releasing hormone. Plasma T3 levels can be “sensed” directly by the anterior pituitary and medial basal hypothalamus; plasma T4 levels require local conversion of T4 to T3, which is mediated by the type 2 deiodinase (D2). To study D2-mediated T4 to T3 conversion and T3 production in the anterior pituitary gland, we used mouse pituitary explants incubated with 125I-T4 for 48 hours to measure T3 production at different concentrations of free T4. The results were compared with cultures of D1- or D2-expressing cells, as well as freshly isolated mouse tissue. These studies revealed a unique regulation of the D2 pathway in the anterior pituitary gland, distinct from that observed in nonpituitary tissues. In the anterior pituitary, increasing T4 levels reduced D2 activity slightly but caused a direct increase in T3 production. However, the same changes in T4 levels decreased T3 production in human HSkM cells and murine C2C12 cells (both skeletal muscle) and mouse bone marrow tissue, which reached zero at 50 pM free T4. In contrast, the increase in T4 levels caused the pig kidney LLC-PK1 cells and kidney fragments to proportionally increase T3 production. These findings have important implications for both physiology and clinical practice because they clarify the mechanism by which fluctuations in plasma T4 levels are transduced in the anterior pituitary gland to mediate the TSH feedback mechanism. LA - English DB - MTMT ER - TY - JOUR AU - Sinkó, Richárd AU - Mohácsik, Petra AU - Fekete, Csaba AU - Gereben, Balázs TI - In vivo Characterization of Endocrine Disrupting Chemical Effects via Thyroid Hormone Action Indicator Mouse JF - JOVE-JOURNAL OF VISUALIZED EXPERIMENTS J2 - JOVE-J VIS EXP VL - 2023 PY - 2023 IS - 200 PG - 10 SN - 1940-087X DO - 10.3791/65657 UR - https://m2.mtmt.hu/api/publication/34232164 ID - 34232164 LA - English DB - MTMT ER - TY - JOUR AU - Salas-Lucia, Federico AU - Fekete, Csaba AU - Sinkó, Richárd AU - Egri, Péter AU - Rada, Kristóf Róbert AU - Ruska, Yvette Magdolna AU - Gereben, Balázs AU - Bianco, Antonio TI - Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain JF - ELIFE J2 - ELIFE VL - 12 PY - 2023 PG - 18 SN - 2050-084X DO - 10.7554/eLife.82683 UR - https://m2.mtmt.hu/api/publication/33917113 ID - 33917113 AB - The development of the brain, as well as mood and cognitive functions, are affected by thyroid hormone (TH) signaling. Neurons are the critical cellular target for TH action, with T3 regulating the expression of important neuronal gene sets. However, the steps involved in T3 signaling remain poorly known given that neurons express high levels of type 3 deiodinase (D3), which inactivates both T4 and T3. To investigate this mechanism, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering T3 to the cell nucleus, and doubling the expression of a T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and D3, which transport and inactivate T3, respectively. Notwithstanding, T3 gets away from degradation because D3's active center is in the cytosol. Moreover, we used a unique mouse system to show that T3 implanted in specific brain areas can trigger selective signaling in distant locations, as far as the contralateral hemisphere. These findings provide a pathway for L-T3 to reach neurons and resolve the paradox of T3 signaling in the brain amid high D3 activity. LA - English DB - MTMT ER - TY - JOUR AU - Kozsurek, Márk AU - Király, Kornél P AU - Gyimesi, Klára AU - Lukácsi, Erika AU - Fekete, Csaba AU - Gereben, Balázs AU - Mohácsik, Petra AU - Helyes, Zsuzsanna AU - Bölcskei, Kata AU - Tékus, Valéria AU - Pap, Károly AU - Szűcs, Edina AU - Benyhe, Sándor AU - Imre, Timea AU - Szabó, Pál Tamás AU - Gajtkó, Andrea AU - Szentesiné Holló, Krisztina AU - Puskár, Zita TI - Unique, Specific CART Receptor-Independent Regulatory Mechanism of CART(55-102) Peptide in Spinal Nociceptive Transmission and Its Relation to Dipeptidyl-Peptidase 4 (DDP4) JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 2 PG - 25 SN - 1661-6596 DO - 10.3390/ijms24020918 UR - https://m2.mtmt.hu/api/publication/33560486 ID - 33560486 AB - Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in astrocytes and consequently reducing neuroinflammation in the rat spinal dorsal horn in a carrageenan-evoked inflammation model. Both naturally occurring CART(55-102) and CART(62-102) peptides are present in the spinal cord. CART(55-102) is not involved in acute nociception but regulates spinal pain transmission during peripheral inflammation. While the full-length peptide with a globular motif contributes to hyperalgesia, its N-terminal inhibits this process. Although the anti-hyperalgesic effects of CART(55-102), CART(55-76), and CART(62-76) are blocked by opioid receptor antagonists in our inflammatory models, but not in neuropathic Seltzer model, none of them bind to any opioid or G-protein coupled receptors. DPP4 interacts with Toll-like receptor 4 (TLR4) signalling in spinal astrocytes and enhances the TLR4-induced expression of interleukin-6 and tumour necrosis factor alpha contributing to inflammatory pain. Depending on the state of inflammation, CART(55-102) is processed in the spinal cord, resulting in the generation of biologically active isoleucine-proline-isoleucine (IPI) tripeptide, which inhibits DPP4, leading to significantly decreased glia-derived cytokine production and hyperalgesia. LA - English DB - MTMT ER - TY - JOUR AU - Sinkó, Richárd AU - Mohácsik, Petra AU - Kővári, Dóra AU - Penksza, Veronika AU - Wittmann, Gábor AU - Borbélyné Mácsai, Lilla AU - Fonseca, Tatiana L AU - Bianco, Antonio Carlos AU - Fekete, Csaba AU - Gereben, Balázs TI - Different hypothalamic mechanisms control decreased circulating thyroid hormone levels in infection and fasting-induced Non-Thyroidal Illness Syndrome in male Thyroid Hormone Action Indicator Mice JF - THYROID J2 - THYROID VL - 33 PY - 2023 IS - 1 SP - 109 EP - 118 PG - 10 SN - 1050-7256 DO - 10.1089/thy.2022.0404 UR - https://m2.mtmt.hu/api/publication/33208795 ID - 33208795 LA - English DB - MTMT ER - TY - JOUR AU - Sinkó, Richárd AU - Rada, Kristóf Róbert AU - Kollár, Anna AU - Mohácsik, Petra AU - Tenk, Miklós AU - Fekete, Csaba AU - Gereben, Balázs TI - Tetrabromobisphenol A and Diclazuril Evoke Tissue-Specific Changes of Thyroid Hormone Signaling in Male Thyroid Hormone Action Indicator Mice JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 23 PG - 16 SN - 1661-6596 DO - 10.3390/ijms232314782 UR - https://m2.mtmt.hu/api/publication/33286458 ID - 33286458 AB - Thyroid hormone (TH) signaling is a prerequisite of normal tissue function. Environmental pollutants with the potential to disrupt endocrine functions represent an emerging threat to human health and agricultural production. We used our Thyroid Hormone Action Indicator (THAI) mouse model to study the effects of tetrabromobisphenol A (TBBPA; 150 mg/bwkg/day orally for 6 days) and diclazuril (10.0 mg/bwkg/day orally for 5 days), a known and a potential hormone disruptor, respectively, on local TH economy. Tissue-specific changes of TH action were assessed in 90-day-old THAI mice by measuring the expression of a TH-responsive luciferase reporter in tissue samples and by in vivo imaging (14-day-long treatment accompanied with imaging on day 7, 14 and 21 from the first day of treatment) in live THAI mice. This was followed by promoter assays to elucidate the mechanism of the observed effects. TBBPA and diclazuril impacted TH action differently and tissue-specifically. TBBPA disrupted TH signaling in the bone and small intestine and impaired the global TH economy by decreasing the circulating free T4 levels. In the promoter assays, TBBPA showed a direct stimulatory effect on the hdio3 promoter, indicating a potential mechanism for silencing TH action. In contrast, diclazuril acted as a stimulator of TH action in the liver, skeletal muscle and brown adipose tissue without affecting the Hypothalamo-Pituitary-Thyroid axis. Our data demonstrate distinct and tissue-specific effects of TBBPA and diclazuril on local TH action and prove that the THAI mouse is a novel mammalian model to identify TH disruptors and their tissue-specific effects. LA - English DB - MTMT ER - TY - JOUR AU - Sánchez-Jaramillo, Edith AU - Wittmann, Gábor AU - Menyhért, Judit AU - Singru, Praful AU - Gómez-González, Gabriela B. AU - Sánchez-Islas, Eduardo AU - Yáñez-Recendis, Nashiely AU - Pimentel-Cabrera, Jaime Arturo AU - León-Olea, Martha AU - Gereben, Balázs AU - Fekete, Csaba AU - Charli, Jean-Louis AU - Lechan, Ronald M. TI - Origin of thyrotropin-releasing hormone neurons that innervate the tuberomammillary nuclei JF - BRAIN STRUCTURE & FUNCTION J2 - BRAIN STRUCT FUNC VL - 227 PY - 2022 IS - 7 SP - 2329 EP - 2347 PG - 19 SN - 1863-2653 DO - 10.1007/s00429-022-02527-5 UR - https://m2.mtmt.hu/api/publication/33128893 ID - 33128893 AB - Hypophysiotropic thyrotropin-releasing hormone (TRH) neurons function as metabolic sensors that regulate the thyroid axis and energy homeostasis. Less is known about the role of other hypothalamic TRH neurons. As central administration of TRH decreases food intake and increases histamine in the tuberomammillary nuclei (TMN), and TMN histamine neurons are densely innervated by TRH fibers from an unknown origin, we mapped the location of TRH neurons that project to the TMN. The retrograde tracer, cholera toxin B subunit (CTB), was injected into the TMN E1–E2, E4–E5 subdivisions of adult Sprague–Dawley male rats. TMN projecting neurons were observed in the septum, preoptic area, bed nucleus of the stria terminalis (BNST), perifornical area, anterior paraventricular nucleus, peduncular and tuberal lateral hypothalamus (TuLH), suprachiasmatic nucleus and medial amygdala. However, CTB/pro-TRH178-199 double-labeled cells were only found in the TuLH. The specificity of the retrograde tract-tracing result was confirmed by administering the anterograde tracer, Phaseolus vulgaris leuco-agglutinin (PHAL) into the TuLH. Double-labeled PHAL-pro-TRH boutons were identified in all subdivisions of the TMN. TMN neurons double-labeled for histidine decarboxylase ( Hdc )/PHAL, Hdc / Trh receptor ( Trhr ), and Hdc / Trh . Further confirmation of a TuLH-TRH neuronal projection to the TMN was established in a transgenic mouse that expresses Cre recombinase in TRH-producing cells following microinjection of a Cre recombinase-dependent AAV that expresses mCherry into the TuLH. We conclude that, in rodents, the TRH innervation of TMN originates in part from TRH neurons in the TuLH, and that this TRH population may contribute to regulate energy homeostasis through histamine Trhr- positive neurons of the TMN. LA - English DB - MTMT ER - TY - JOUR AU - Liu, Shengnan AU - Shen, Siyi AU - Yan, Ying AU - Sun, Chao AU - Lu, Zhiqiang AU - Feng, Hua AU - Ma, Yiruo AU - Tang, Zhili AU - Yu, Jing AU - Wu, Yuting AU - Gereben, Balázs AU - Mohácsik, Petra AU - Fekete, Csaba AU - Feng, Xiaoyun AU - Yuan, Feixiang AU - Guo, Feifan AU - Hu, Cheng AU - Shao, Mengle AU - Gao, Xin AU - Zhao, Lin AU - Li, Yuying AU - Jiang, Jingjing AU - Ying, Hao TI - Triiodothyronine (T3) promotes brown fat hyperplasia via thyroid hormone receptor α mediated adipocyte progenitor cell proliferation JF - NATURE COMMUNICATIONS J2 - NAT COMMUN VL - 13 PY - 2022 IS - 1 SN - 2041-1723 DO - 10.1038/s41467-022-31154-1 UR - https://m2.mtmt.hu/api/publication/32886731 ID - 32886731 LA - English DB - MTMT ER - TY - JOUR AU - Kővári, Dóra AU - Penksza, Veronika AU - Stiftné Szilvásy-Szabó, Anett AU - Sinkó, Richárd AU - Gereben, Balázs AU - Mackie, Ken AU - Fekete, Csaba TI - Tanycyte specific ablation of diacylglycerol lipase alpha stimulates the hypothalamic‐pituitary‐thyroid axis by decreasing the endocannabinoid mediated inhibition of TRH release JF - JOURNAL OF NEUROENDOCRINOLOGY J2 - J NEUROENDOCRINOL VL - 34 PY - 2022 IS - 1 PG - 9 SN - 0953-8194 DO - 10.1111/jne.13079 UR - https://m2.mtmt.hu/api/publication/32583377 ID - 32583377 N1 - Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary János Szentágothai Doctoral School of Neurosciences, Neuroendocrinology Program, Semmelweis University, Budapest, Hungary Laboratory of Molecular Cell Metabolism, Institute of Experimental Medicine, Budapest, Hungary Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States Cited By :2 Export Date: 15 May 2023 CODEN: JOUNE Correspondence Address: Fekete, C.; Laboratory of Integrative Neuroendocrinology, Hungary; email: fekete.csaba@koki.hu Chemicals/CAS: glucose, 50-99-7, 84778-64-3; lipoprotein lipase, 83137-80-8, 9004-02-8; protirelin, 24305-27-9; tamoxifen, 10540-29-1; thyroxine, 7488-70-2; Endocannabinoids; Lipoprotein Lipase; Thyrotropin-Releasing Hormone Funding details: 2017‐1.2.1‐NKP‐2017‐00002 Funding details: Johns Hopkins University, JHU Funding details: Horizon 2020 Framework Programme, H2020, 666869 Funding details: Hungarian Scientific Research Fund, OTKA, K124767, K125247 Funding details: Hungarian Science Foundation Funding text 1: This work was supported by Grants from the Hungarian National Brain Research Program (2017‐1.2.1‐NKP‐2017‐00002), EU H2020 THYRAGE no. 666869 and the Hungarian Science Foundation (OTKA K124767, K125247). The authors are very grateful to Professor Andreas Zimmer (Institute of Molecular Psychiatry University of Bonn, Germany) and Professor Seth Blackshaw (Johns Hopkins University, Baltimore, MD, United States) for the kind gift of Dagla and Rax‐CreERT2 mice, respectively. The technical assistance of Andrea Juhász is gratefully acknowleged. fl/fl Funding text 2: This work was supported by Grants from the Hungarian National Brain Research Program (2017-1.2.1-NKP-2017-00002), EU H2020 THYRAGE no. 666869 and the Hungarian Science Foundation (OTKA K124767, K125247). The authors are very grateful to Professor Andreas Zimmer (Institute of Molecular Psychiatry University of Bonn, Germany) and Professor Seth Blackshaw (Johns Hopkins University, Baltimore, MD, United States) for the kind gift of Daglafl/fl and Rax-CreERT2 mice, respectively. The technical assistance of Andrea Juhász is gratefully acknowleged. LA - English DB - MTMT ER -