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1.
Nature ; 628(8009): 826-834, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38538787

RESUMEN

Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized1. Tanycytes are a specialized cell type along the wall of the third ventricle2 that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system3-8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.


Asunto(s)
Tronco Encefálico , Células Ependimogliales , Conducta Alimentaria , Calor , Hipotálamo , Vías Nerviosas , Neuronas , Animales , Femenino , Masculino , Ratones , Proteína Relacionada con Agouti/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/citología , Tronco Encefálico/citología , Tronco Encefálico/fisiología , Dopamina/metabolismo , Ingestión de Alimentos/fisiología , Células Ependimogliales/citología , Células Ependimogliales/fisiología , Conducta Alimentaria/fisiología , Ácido Glutámico/metabolismo , Hipotálamo/citología , Hipotálamo/fisiología , Vías Nerviosas/metabolismo , Neuronas/metabolismo , Núcleos Parabraquiales/citología , Núcleos Parabraquiales/metabolismo , Núcleos Parabraquiales/fisiología , Sensación Térmica/fisiología , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/líquido cefalorraquídeo , Factor A de Crecimiento Endotelial Vascular/metabolismo
2.
Front Neuroendocrinol ; 75: 101154, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-39226950

RESUMEN

Astrocytes are now recognized as integral components of neural circuits, regulating their maturation, activity and plasticity. Neuroendocrinology has provided fertile ground for revealing the diverse strategies used by astrocytes to regulate the physiological and behavioural outcomes of neural circuit activity in response to internal and environmental inputs. However, the development of astrocytes in the hypothalamus has received much less attention than in other brain regions such as the cerebral cortex and spinal cord. In this review, we synthesize our current knowledge of astrogenesis in the hypothalamus across various life stages. A distinctive feature of hypothalamic astrogenesis is that it persists all throughout lifespan, and involves multiple cellular sources corresponding to radial glial cells during early development, followed by tanycytes, parenchymal progenitors and locally dividing astrocytes. Astrogenesis in the hypothalamus is closely coordinated with the maturation of hypothalamic neurons. This coordination is exemplified by recent findings in neurons producing gonadotropin-releasing hormone, which actively shape their astroglial environment during infancy to integrate functionally into their neural network and facilitate sexual maturation, a process vulnerable to endocrine disruption. While hypothalamic astrogenesis shares common principles with other brain regions, it also exhibits specific features in its dynamics and regulation, both at the inter- and intra-regional levels. These unique properties emphasize the importance of further exploration. Additionally, we discuss the experimental strategies used to assess astrogenesis in the hypothalamus and their potential bias and limitations. Understanding the mechanisms of hypothalamic astrogenesis throughout life will be crucial for comprehending the development and function of the hypothalamus under both physiological and pathological conditions.

3.
Development ; 149(19)2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-36239412

RESUMEN

The binding of 17ß-oestradiol to oestrogen receptor alpha (ERα) plays a crucial role in the control of reproduction, acting through both nuclear and membrane-initiated signalling. To study the physiological role of membrane ERα in the reproductive system, we used the C451A-ERα mouse model with selective loss of function of membrane ERα. Despite C451A-ERα mice being described as sterile, daily weighing and ultrasound imaging revealed that homozygous females do become pregnant, allowing the investigation of the role of ERα during pregnancy for the first time. All neonatal deaths of the mutant offspring mice resulted from delayed parturition associated with failure in pre-term progesterone withdrawal. Moreover, pregnant C451A-ERα females exhibited partial intrauterine embryo arrest at about E9.5. The observed embryonic lethality resulted from altered expansion of Tpbpa-positive spiral artery-associated trophoblast giant cells into the utero-placental unit, which is associated with an imbalance in expression of angiogenic factors. Together, these processes control the trophoblast-mediated spiral arterial remodelling. Hence, loss of membrane ERα within maternal tissues clearly alters the activity of invasive trophoblast cells during placentogenesis. This previously unreported function of membrane ERα could open new avenues towards a better understanding of human pregnancy-associated pathologies.


Asunto(s)
Receptor alfa de Estrógeno , Trofoblastos , Animales , Estradiol/metabolismo , Receptor alfa de Estrógeno/genética , Femenino , Fertilidad , Humanos , Ratones , Placenta/metabolismo , Embarazo , Progesterona/metabolismo , Receptores de Estrógenos/metabolismo , Trofoblastos/metabolismo
4.
Hepatology ; 2024 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-38761407

RESUMEN

BACKGROUND AND AIMS: Mitochondrial antiviral signaling protein (MAVS) is a critical regulator that activates the host's innate immunity against RNA viruses, and its signaling pathway has been linked to the secretion of proinflammatory cytokines. However, the actions of MAVS on inflammatory pathways during the development of metabolic dysfunction-associated steatotic liver disease (MASLD) have been little studied. APPROACH AND RESULTS: Liver proteomic analysis of mice with genetically manipulated hepatic p63, a transcription factor that induces liver steatosis, revealed MAVS as a target downstream of p63. MAVS was thus further evaluated in liver samples from patients and in animal models with MASLD. Genetic inhibition of MAVS was performed in hepatocyte cell lines, primary hepatocytes, spheroids, and mice. MAVS expression is induced in the liver of both animal models and people with MASLD as compared with those without liver disease. Using genetic knockdown of MAVS in adult mice ameliorates diet-induced MASLD. In vitro, silencing MAVS blunts oleic and palmitic acid-induced lipid content, while its overexpression increases the lipid load in hepatocytes. Inhibiting hepatic MAVS reduces circulating levels of the proinflammatory cytokine TNFα and the hepatic expression of both TNFα and NFκß. Moreover, the inhibition of ERK abolished the activation of TNFα induced by MAVS. The posttranslational modification O -GlcNAcylation of MAVS is required to activate inflammation and to promote the high lipid content in hepatocytes. CONCLUSIONS: MAVS is involved in the development of steatosis, and its inhibition in previously damaged hepatocytes can ameliorate MASLD.

5.
Proc Natl Acad Sci U S A ; 119(30): e2203503119, 2022 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-35867816

RESUMEN

Women with polycystic ovary syndrome (PCOS) frequently experience decreased sexual arousal, desire, and sexual satisfaction. While the hypothalamus is known to regulate sexual behavior, the specific neuronal pathways affected in patients with PCOS are not known. To dissect the underlying neural circuitry, we capitalized on a robust preclinical animal model that reliably recapitulates all cardinal PCOS features. We discovered that female mice prenatally treated with anti-Müllerian hormone (PAMH) display impaired sexual behavior and sexual partner preference over the reproductive age. Blunted female sexual behavior was associated with increased sexual rejection and independent of sex steroid hormone status. Structurally, sexual dysfunction was associated with a substantial loss of neuronal nitric oxide synthase (nNOS)-expressing neurons in the ventromedial nucleus of the hypothalamus (VMH) and other areas of hypothalamic nuclei involved in social behaviors. Using in vivo chemogenetic manipulation, we show that nNOSVMH neurons are required for the display of normal sexual behavior in female mice and that pharmacological replenishment of nitric oxide restores normal sexual performance in PAMH mice. Our data provide a framework to investigate facets of hypothalamic nNOS neuron biology with implications for sexual disturbances in PCOS.


Asunto(s)
Óxido Nítrico Sintasa de Tipo I , Óxido Nítrico , Síndrome del Ovario Poliquístico , Conducta Sexual , Núcleo Hipotalámico Ventromedial , Animales , Hormona Antimülleriana/farmacología , Modelos Animales de Enfermedad , Femenino , Preferencia en el Apareamiento Animal , Ratones , Neuronas/efectos de los fármacos , Neuronas/enzimología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Síndrome del Ovario Poliquístico/enzimología , Síndrome del Ovario Poliquístico/fisiopatología , Núcleo Hipotalámico Ventromedial/efectos de los fármacos , Núcleo Hipotalámico Ventromedial/metabolismo
6.
EMBO J ; 39(19): e104633, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32761635

RESUMEN

Hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH), the "master molecule" regulating reproduction and fertility, migrate from their birthplace in the nose to their destination using a system of guidance cues, which include the semaphorins and their receptors, the neuropilins and plexins, among others. Here, we show that selectively deleting neuropilin-1 in new GnRH neurons enhances their survival and migration, resulting in excess neurons in the hypothalamus and in their unusual accumulation in the accessory olfactory bulb, as well as an acceleration of mature patterns of activity. In female mice, these alterations result in early prepubertal weight gain, premature attraction to male odors, and precocious puberty. Our findings suggest that rather than being influenced by peripheral energy state, GnRH neurons themselves, through neuropilin-semaphorin signaling, might engineer the timing of puberty by regulating peripheral adiposity and behavioral switches, thus acting as a bridge between the reproductive and metabolic axes.


Asunto(s)
Regulación de la Expresión Génica , Hormona Liberadora de Gonadotropina/metabolismo , Neuronas/metabolismo , Neuropilina-1/biosíntesis , Conducta Sexual Animal , Maduración Sexual , Aumento de Peso , Animales , Femenino , Hormona Liberadora de Gonadotropina/genética , Masculino , Ratones , Ratones Transgénicos , Neuropilina-1/genética
7.
Gut ; 72(3): 472-483, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-35580962

RESUMEN

OBJECTIVE: p63 is a transcription factor within the p53 protein family that has key roles in development, differentiation and prevention of senescence, but its metabolic actions remain largely unknown. Herein, we investigated the physiological role of p63 in glucose metabolism. DESIGN: We used cell lines and mouse models to genetically manipulate p63 in hepatocytes. We also measured p63 in the liver of patients with obesity with or without type 2 diabetes (T2D). RESULTS: We show that hepatic p63 expression is reduced on fasting. Mice lacking the specific isoform TAp63 in the liver (p63LKO) display higher postprandial and pyruvate-induced glucose excursions. These mice have elevated SIRT1 levels, while SIRT1 knockdown in p63LKO mice normalises glycaemia. Overexpression of TAp63 in wild-type mice reduces postprandial, pyruvate-induced blood glucose and SIRT1 levels. Studies carried out in hepatocyte cell lines show that TAp63 regulates SIRT1 promoter by repressing its transcriptional activation. TAp63 also mediates the inhibitory effect of insulin on hepatic glucose production, as silencing TAp63 impairs insulin sensitivity. Finally, protein levels of TAp63 are reduced in obese persons with T2D and are negatively correlated with fasting glucose and homeostasis model assessment index. CONCLUSIONS: These results demonstrate that p63 physiologically regulates glucose homeostasis.


Asunto(s)
Diabetes Mellitus Tipo 2 , Sirtuina 1 , Transactivadores , Animales , Ratones , Glucosa/metabolismo , Hígado/metabolismo , Piruvatos/metabolismo , Sirtuina 1/metabolismo , Transactivadores/metabolismo
8.
Brain ; 145(12): 4264-4274, 2022 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-35929549

RESUMEN

A genetic deficiency of the solute carrier monocarboxylate transporter 8 (MCT8), termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. MCT8 transports thyroid hormones across cell membranes. While thyroid hormone analogues improve peripheral changes of MCT8 deficiency, no treatment of the neurological symptoms is available so far. Therefore, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased tri-iodothyronine (T3) levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.


Asunto(s)
Personas con Discapacidad , Discapacidad Intelectual Ligada al Cromosoma X , Trastornos Motores , Simportadores , Ratones , Animales , Humanos , Barrera Hematoencefálica/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Hipotonía Muscular/genética , Atrofia Muscular , Células Endoteliales/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Hormonas Tiroideas/metabolismo , Terapia Genética , Simportadores/genética , Simportadores/metabolismo
9.
Cell Mol Life Sci ; 79(7): 361, 2022 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-35697820

RESUMEN

COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Melatonina , Enzima Convertidora de Angiotensina 2 , Animales , Encéfalo/metabolismo , Células Endoteliales/metabolismo , Melatonina/farmacología , Melatonina/uso terapéutico , Ratones , Ratones Transgénicos , Peptidil-Dipeptidasa A , SARS-CoV-2
10.
Reprod Domest Anim ; 58 Suppl 2: 109-124, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37329313

RESUMEN

Pulsatile secretion of gonadotropin-releasing hormone (GnRH) is essential for the activation and maintenance of the function of the hypothalamic-pituitary-gonadal (HPG) axis, which controls the onset of puberty and fertility. Two provocative recent studies suggest that, in addition to control reproduction, the neurons in the brain that produce GnRH are also involved in the control postnatal brain maturation, odour discrimination and adult cognition. Long-acting GnRH antagonists and agonists are commonly used to control fertility and behaviour in veterinary medicine, primarily in males. This review puts into perspective the potential risks of these androgen deprivation therapies and immunization on olfactory and cognitive performances and well-aging in domestic animals, including pets. We will also discuss the results reporting beneficial effects of pharmacological interventions restoring physiological GnRH levels on olfactory and cognitive alterations in preclinical models of Alzheimer's disease, which shares many pathophysiological and behavioural hallmarks with canine cognitive dysfunction. These novel findings raise the intriguing possibility that pulsatile GnRH therapy holds therapeutic potential for the management of this behavioural syndrome affecting older dogs.


Asunto(s)
Enfermedades de los Perros , Neoplasias de la Próstata , Masculino , Animales , Perros , Hormona Liberadora de Gonadotropina , Olfato , Antagonistas de Andrógenos , Neoplasias de la Próstata/veterinaria , Cognición
11.
J Hepatol ; 77(1): 15-28, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35167910

RESUMEN

BACKGROUND & AIMS: The pathogenesis of liver fibrosis requires activation of hepatic stellate cells (HSCs); once activated, HSCs lose intracellular fatty acids but the role of fatty acid oxidation and carnitine palmitoyltransferase 1A (CPT1A) in this process remains largely unexplored. METHODS: CPT1A was found in HSCs of patients with fibrosis. Pharmacological and genetic manipulation of CPT1A were performed in human HSC cell lines and primary HCSs. Finally, we induced fibrosis in mice lacking CPT1A specifically in HSCs. RESULTS: Herein, we show that CPT1A expression is elevated in HSCs of patients with non-alcoholic steatohepatitis, showing a positive correlation with the fibrosis score. This was corroborated in rodents with fibrosis, as well as in primary human HSCs and LX-2 cells activated by transforming growth factor ß1 (TGFß1) and fetal bovine serum (FBS). Furthermore, both pharmacological and genetic silencing of CPT1A prevent TGFß1- and FBS-induced HSC activation by reducing mitochondrial activity. The overexpression of CPT1A, induced by saturated fatty acids and reactive oxygen species, triggers mitochondrial activity and the expression of fibrogenic markers. Finally, mice lacking CPT1A specifically in HSCs are protected against fibrosis induced by a choline-deficient high-fat diet, a methionine- and choline-deficient diet, or treatment with carbon tetrachloride. CONCLUSIONS: These results indicate that CPT1A plays a critical role in the activation of HSCs and is implicated in the development of liver fibrosis, making it a potentially actionable target for fibrosis treatment. LAY SUMMARY: We show that the enzyme carnitine palmitoyltransferase 1A (CPT1A) is elevated in hepatic stellate cells (HSCs) in patients with fibrosis and mouse models of fibrosis, and that CPT1A induces the activation of these cells. Inhibition of CPT1A ameliorates fibrosis by preventing the activation of HSCs.


Asunto(s)
Carnitina O-Palmitoiltransferasa , Células Estrelladas Hepáticas , Animales , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Colina , Ácidos Grasos/metabolismo , Fibrosis , Células Estrelladas Hepáticas/metabolismo , Humanos , Hígado/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/prevención & control , Ratones
12.
J Hepatol ; 76(1): 11-24, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34555423

RESUMEN

BACKGROUND & AIMS: Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to non-alcoholic fatty liver disease (NAFLD) remains unknown. METHODS: By performing proteomic analysis on livers from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples from patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the livers of mice. RESULTS: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and non-alcoholic steatohepatitis) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoyltransferase 1a (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action. CONCLUSIONS: Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis. LAY SUMMARY: We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD by stimulating mitochondrial function. Thus, ATG3 is an important factor implicated in steatosis.


Asunto(s)
Proteínas Relacionadas con la Autofagia/antagonistas & inhibidores , Hígado Graso/prevención & control , Mitocondrias Hepáticas/metabolismo , Enzimas Ubiquitina-Conjugadoras/antagonistas & inhibidores , Animales , Proteínas Relacionadas con la Autofagia/farmacología , Modelos Animales de Enfermedad , Hígado Graso/fisiopatología , Metabolismo de los Lípidos/genética , Ratones , Mitocondrias Hepáticas/fisiología , Proteómica/métodos , Enzimas Ubiquitina-Conjugadoras/farmacología
13.
Clin Endocrinol (Oxf) ; 97(1): 52-63, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35470446

RESUMEN

INTRODUCTION: Few studies have attempted to evaluate the early efficacy of first-generation somatostatin analogues in somatotroph macroadenomas. OBJECTIVE: To investigate the short-term efficacy of primary therapy with lanreotide 120 mg at 1 and 3 months on tumour shrinkage and ophthalmologic symptoms in newly diagnosed patients with acromegaly. DESIGN AND PATIENTS: This single-centre retrospective study included 21 patients with de novo acromegaly resulting from pituitary macroadenoma, with optic chiasm compression (Grade ≤ 2) and/or cavernous sinus invasion, treated with a monthly injection of lanreotide 120 mg. Clinical, hormonal, ophthalmologic and magnetic resonance imaging scan evaluations were conducted after the first and the third months of treatment. RESULTS: Tumour volume reduction was more pronounced at 1 month; mean volume change: -31.4 ± 19.5%, p < .0001 than between the first and third month of treatment; mean volume reduction: -20.6 ± 13.4%, p = .0009. The mean volume change between baseline and the third month was - 46.4 ± 21.6, (p < .0001). A significant volume reduction (≥25%) was observed in 61.9% of individuals (13/21) at the first month. Among 14 individuals with optic chiasm compression and visual field defects, visual field normalization or improvement were observed in seven cases (50%), stabilization in four cases (28.5%), and mild worsening in three cases (21.4%) at 1 month. The decrease in growth hormone and IGF-1 serum values was significant at 1 month. CONCLUSIONS: Primary treatment with lanreotide 120 mg in patients with somatotroph macroadenomas provides early significant tumour shrinkage with rapid improvement of visual symptoms at the end of the first month in 50% of patients.


Asunto(s)
Acromegalia , Hormona de Crecimiento Humana , Neoplasias Hipofisarias , Acromegalia/tratamiento farmacológico , Preparaciones de Acción Retardada/uso terapéutico , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina , Péptidos Cíclicos , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/tratamiento farmacológico , Estudios Retrospectivos , Somatostatina/análogos & derivados
14.
PLoS Biol ; 17(11): e3000532, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31697675

RESUMEN

Mkrn3, the maternally imprinted gene encoding the makorin RING-finger protein-3, has recently emerged as putative pubertal repressor, as evidenced by central precocity caused by MKRN3 mutations in humans; yet, the molecular underpinnings of this key regulatory action remain largely unexplored. We report herein that the microRNA, miR-30, with three binding sites in a highly conserved region of its 3' UTR, operates as repressor of Mkrn3 to control pubertal onset. Hypothalamic miR-30b expression increased, while Mkrn3 mRNA and protein content decreased, during rat postnatal maturation. Neonatal estrogen exposure, causing pubertal alterations, enhanced hypothalamic Mkrn3 and suppressed miR-30b expression in female rats. Functional in vitro analyses demonstrated a strong repressive action of miR-30b on Mkrn3 3' UTR. Moreover, central infusion during the juvenile period of target site blockers, tailored to prevent miR-30 binding to Mkrn3 3' UTR, reversed the prepubertal down-regulation of hypothalamic Mkrn3 protein and delayed female puberty. Collectively, our data unveil a novel hypothalamic miRNA pathway, involving miR-30, with a prominent role in the control of puberty via Mkrn3 repression. These findings expand our current understanding of the molecular basis of puberty and its disease states.


Asunto(s)
Hipotálamo/metabolismo , MicroARNs/fisiología , Maduración Sexual/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Sitios de Unión , Línea Celular , Femenino , Regulación del Desarrollo de la Expresión Génica , Masculino , MicroARNs/metabolismo , Ratas , Análisis de Secuencia de ADN
15.
Glia ; 69(5): 1079-1093, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33105065

RESUMEN

The contribution of neuroglial interactions to the regulation of energy balance has gained increasing acceptance in recent years. In this context, endozepines, endogenous analogs of benzodiazepine derived from diazepam-binding inhibitor, are now emerging as major players. Produced by glial cells (astrocytes and tanycytes), endozepines have been known for two decades to exert potent anorexigenic effects by acting at the hypothalamic level. However, it is only recently that their modes of action, including the mechanisms by which they modulate energy metabolism, have begun to be elucidated. The data available today are abundant, significant, and sometimes contradictory, revealing a much more complex regulation than initially expected. Several mechanisms of action of endozepines seem to coexist at the central level, particularly in the hypothalamus. The brainstem has also recently emerged as a potential site of action for endozepines. In addition to their central anorexigenic effects, endozepines may also display peripheral effects promoting orexigenic actions, adding to their complexity and raising yet more questions. In this review, we attempt to provide an overview of our current knowledge in this rapidly evolving field and to pinpoint questions that remain unanswered.


Asunto(s)
Inhibidor de la Unión a Diazepam , Neuroglía , Inhibidor de la Unión a Diazepam/metabolismo , Metabolismo Energético , Hipotálamo/metabolismo , Neuroglía/metabolismo , Péptidos
16.
Neuroendocrinology ; 111(4): 370-387, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32335558

RESUMEN

INTRODUCTION: Metabolic dysfunction is now recognized as a pivotal component of Alzheimer's disease (AD), the most common dementia worldwide. However, the precise molecular mechanisms linking metabolic dysfunction to AD remain elusive. OBJECTIVE: Here, we investigated the direct impact of soluble oligomeric amyloid beta (Aß) peptides, the main molecular hallmark of AD, on the leptin system, a major component of central energy metabolism regulation. METHODS: We developed a new time-resolved fluorescence resonance energy transfer-based Aß binding assay for the leptin receptor (LepR) and studied the effect of Aß on LepR function in several in vitro assays. The in vivo effect of Aß on LepR function was studied in an Aß-specific AD mouse model and in pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus. RESULTS: We revealed specific and high-affinity (Ki = 0.1 nM) binding of Aß to LepR. Pharmacological characterization of this interaction showed that Aß binds allosterically to the extracellular domain of LepR and negatively affects receptor function. Negative allosteric modulation of LepR by Aß was detected at the level of signaling pathways (STAT-3, AKT, and ERK) in vitroand in vivo. Importantly, the leptin-induced response of POMC neurons, key players in the regulation of metabolic function, was completely abolished in the presence of Aß. CONCLUSION: Our data indicate that Aß is a negative allosteric modulator of LepR, resulting in impaired leptin action, and qualify LepR as a new and direct target of Aß oligomers. Preventing the interaction of Aß with LepR might improve both the metabolic and cognitive dysfunctions in AD condition.


Asunto(s)
Regulación Alostérica/fisiología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Leptina/metabolismo , Proopiomelanocortina/metabolismo , Receptores de Leptina/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Masculino , Ratones , Transducción de Señal/fisiología
17.
Cell Mol Life Sci ; 77(24): 5189-5205, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31900622

RESUMEN

Transmission of extracellular signals by G protein-coupled receptors typically relies on a cascade of intracellular events initiated by the activation of heterotrimeric G proteins or ß-arrestins followed by effector activation/inhibition. Here, we report an alternative signal transduction mode used by the orphan GPR50 that relies on the nuclear translocation of its carboxyl-terminal domain (CTD). Activation of the calcium-dependent calpain protease cleaves off the CTD from the transmembrane-bound GPR50 core domain between Phe-408 and Ser-409 as determined by MALDI-TOF-mass spectrometry. The cytosolic CTD then translocates into the nucleus assisted by its 'DPD' motif, where it interacts with the general transcription factor TFII-I to regulate c-fos gene transcription. RNA-Seq analysis indicates a broad role of the CTD in modulating gene transcription with ~ 8000 differentially expressed genes. Our study describes a non-canonical, direct signaling mode of GPCRs to the nucleus with similarities to other receptor families such as the NOTCH receptor.


Asunto(s)
Proteínas del Tejido Nervioso/genética , Transporte de Proteínas/genética , Receptores Acoplados a Proteínas G/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Humanos , Unión Proteica/genética , Receptores Notch , Transducción de Señal/genética , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
18.
Int J Mol Sci ; 22(9)2021 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-34066779

RESUMEN

The mechanisms underlying the transport of leptin into the brain are still largely unclear. While the leptin receptor has been implicated in the transport process, recent evidence has suggested an additional role of LRP2 (megalin). To evaluate the function of LRP2 for leptin transport across the blood-brain barrier (BBB), we developed a novel leptin-luciferase fusion protein (pLG), which stimulated leptin signaling and was transported in an in vitro BBB model based on porcine endothelial cells. The LRP inhibitor RAP did not affect leptin transport, arguing against a role of LRP2. In line with this, the selective deletion of LRP2 in brain endothelial cells and epithelial cells of the choroid plexus did not influence bodyweight, body composition, food intake, or energy expenditure of mice. These findings suggest that LRP2 at the BBB is not involved in the transport of leptin into the brain, nor in the development of obesity as has previously been described.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Leptina/metabolismo , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Obesidad/metabolismo , Obesidad/patología , Animales , Sitios de Unión , Composición Corporal , Peso Corporal , Células CHO , Plexo Coroideo/metabolismo , Cricetulus , Células Endoteliales/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Luciferasas/metabolismo , Masculino , Modelos Biológicos , Fosforilación , Transporte de Proteínas , Receptores de Leptina/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Porcinos
19.
Neuroendocrinology ; 110(6): 552-562, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31484186

RESUMEN

The hypothalamus contains integrative systems that support life, including physiological processes such as food intake, energy expenditure, and reproduction. Here, we show that anorexia nervosa (AN) patients, contrary to normal weight and constitutionally lean individuals, respond with a paradoxical reduction in hypothalamic levels of glutamate/glutamine (Glx) upon feeding. This reversal of the Glx response is associated with decreased wiring in the arcuate nucleus and increased connectivity in the lateral hypothalamic area, which are involved in the regulation on a variety of physiological and behavioral functions including the control of food intake and energy balance. The identification of distinct hypothalamic neurochemical dysfunctions and associated structural variations in AN paves the way for the development of new diagnostic and treatment strategies in conditions associated with abnormal body mass index and a maladaptive response to negative energy balance.


Asunto(s)
Anorexia Nerviosa , Núcleo Arqueado del Hipotálamo , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Área Hipotalámica Lateral , Adulto , Anorexia Nerviosa/diagnóstico por imagen , Anorexia Nerviosa/metabolismo , Anorexia Nerviosa/patología , Anorexia Nerviosa/fisiopatología , Núcleo Arqueado del Hipotálamo/diagnóstico por imagen , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/patología , Núcleo Arqueado del Hipotálamo/fisiopatología , Femenino , Humanos , Área Hipotalámica Lateral/diagnóstico por imagen , Área Hipotalámica Lateral/metabolismo , Área Hipotalámica Lateral/patología , Área Hipotalámica Lateral/fisiopatología , Imagen por Resonancia Magnética , Masculino , Espectroscopía de Protones por Resonancia Magnética , Adulto Joven
20.
Development ; 143(21): 3969-3981, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-27803058

RESUMEN

Fertility in mammals is controlled by hypothalamic neurons that secrete gonadotropin-releasing hormone (GnRH). These neurons differentiate in the olfactory placodes during embryogenesis and migrate from the nose to the hypothalamus before birth. Information regarding this process in humans is sparse. Here, we adapted new tissue-clearing and whole-mount immunohistochemical techniques to entire human embryos/fetuses to meticulously study this system during the first trimester of gestation in the largest series of human fetuses examined to date. Combining these cutting-edge techniques with conventional immunohistochemistry, we provide the first chronological and quantitative analysis of GnRH neuron origins, differentiation and migration, as well as a 3D atlas of their distribution in the fetal brain. We reveal not only that the number of GnRH-immunoreactive neurons in humans is significantly higher than previously thought, but that GnRH cells migrate into several extrahypothalamic brain regions in addition to the hypothalamus. Their presence in these areas raises the possibility that GnRH has non-reproductive roles, creating new avenues for research on GnRH functions in cognitive, behavioral and physiological processes.


Asunto(s)
Encéfalo/embriología , Diferenciación Celular , Movimiento Celular , Fertilidad/fisiología , Feto/citología , Hormona Liberadora de Gonadotropina/metabolismo , Neuronas/fisiología , Anatomía Artística , Atlas como Asunto , Encéfalo/citología , Encéfalo/metabolismo , Mapeo Encefálico/métodos , Embrión de Mamíferos , Desarrollo Embrionario/fisiología , Femenino , Feto/embriología , Feto/metabolismo , Humanos , Imagenología Tridimensional , Inmunohistoquímica , Masculino , Neuronas/metabolismo
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