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1.
Proc Natl Acad Sci U S A ; 118(15)2021 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-33827930

RESUMEN

The ventromedial hypothalamus (VMH) is a critical neural node that senses blood glucose and promotes glucose utilization or mobilization during hypoglycemia. The VMH neurons that control these distinct physiologic processes are largely unknown. Here, we show that melanocortin 3 receptor (Mc3R)-expressing VMH neurons (VMHMC3R) sense glucose changes both directly and indirectly via altered excitatory input. We identify presynaptic nodes that potentially regulate VMHMC3R neuronal activity, including inputs from proopiomelanocortin (POMC)-producing neurons in the arcuate nucleus. We find that VMHMC3R neuron activation blunts, and their silencing enhances glucose excursion following a glucose load. Overall, these findings demonstrate that VMHMC3R neurons are a glucose-responsive hypothalamic subpopulation that promotes glucose disposal upon activation; this highlights a potential site for targeting dysregulated glycemia.


Asunto(s)
Glucosa/metabolismo , Hiperglucemia/metabolismo , Hipotálamo/metabolismo , Neuronas/metabolismo , Receptor de Melanocortina Tipo 3/metabolismo , Animales , Hipotálamo/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/fisiología , Proopiomelanocortina/metabolismo , Receptor de Melanocortina Tipo 3/genética , Potenciales Sinápticos
2.
Nature ; 507(7491): 238-42, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24487620

RESUMEN

Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.


Asunto(s)
Proteína Relacionada con Agouti/metabolismo , Hambre/fisiología , Vías Nerviosas/fisiología , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/fisiología , Proteína Relacionada con Agouti/deficiencia , Animales , Apetito/efectos de los fármacos , Apetito/fisiología , Núcleo Arqueado del Hipotálamo/citología , Núcleo Arqueado del Hipotálamo/metabolismo , Mapeo Encefálico , Rastreo Celular , Clozapina/análogos & derivados , Clozapina/farmacología , Dependovirus/genética , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Femenino , Privación de Alimentos , Hambre/efectos de los fármacos , Integrasas/metabolismo , Masculino , Ratones , Vías Nerviosas/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Neuronas/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Fragmentos de Péptidos/deficiencia , Fragmentos de Péptidos/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Virus de la Rabia/genética , Respuesta de Saciedad/fisiología , Hormona Liberadora de Tirotropina/metabolismo
3.
J Neurosci ; 34(46): 15306-18, 2014 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-25392498

RESUMEN

The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of Sim1-expressing cell types that comprise a major autonomic output nucleus and play critical roles in the control of food intake and energy homeostasis. The roles of specific PVH neuronal subtypes in energy balance have yet to be defined, however. The PVH contains nitric oxide synthase-1 (Nos1)-expressing (Nos1(PVH)) neurons of unknown function; these represent a subset of the larger population of Sim1-expressing PVH (Sim1(PVH)) neurons. To determine the role of Nos1(PVH) neurons in energy balance, we used Cre-dependent viral vectors to both map their efferent projections and test their functional output in mice. Here we show that Nos1(PVH) neurons project to hindbrain and spinal cord regions important for food intake and energy expenditure control. Moreover, pharmacogenetic activation of Nos1(PVH) neurons suppresses feeding to a similar extent as Sim1(PVH) neurons, and increases energy expenditure and activity. Furthermore, we found that oxytocin-expressing PVH neurons (OXT(PVH)) are a subset of Nos1(PVH) neurons. OXT(PVH) cells project to preganglionic, sympathetic neurons in the thoracic spinal cord and increase energy expenditure upon activation, though not to the same extent as Nos1(PVH) neurons; their activation fails to alter feeding, however. Thus, Nos1(PVH) neurons promote negative energy balance through changes in feeding and energy expenditure, whereas OXT(PVH) neurons regulate energy expenditure alone, suggesting a crucial role for non-OXT Nos1(PVH) neurons in feeding regulation.


Asunto(s)
Regulación del Apetito/fisiología , Metabolismo Energético/fisiología , Neuronas/fisiología , Óxido Nítrico Sintasa de Tipo I/fisiología , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/fisiología , Animales , Regulación del Apetito/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Temperatura Corporal/fisiología , Ingestión de Alimentos/fisiología , Metabolismo Energético/genética , Masculino , Ratones , Ratones Transgénicos , Vías Nerviosas/citología , Vías Nerviosas/fisiología , Técnicas de Trazados de Vías Neuroanatómicas , Óxido Nítrico Sintasa de Tipo I/genética , Oxitocina/fisiología , Núcleo Hipotalámico Paraventricular/anatomía & histología , Proteínas Represoras/fisiología , Rombencéfalo/anatomía & histología , Rombencéfalo/citología , Rombencéfalo/fisiología , Médula Espinal/anatomía & histología , Médula Espinal/citología , Médula Espinal/fisiología
4.
Endocrinology ; 160(2): 343-358, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30541071

RESUMEN

The central melanocortin system plays a crucial role in the control of energy balance. Although the decreased energy expenditure and increased adiposity of melanocortin-3 receptor (Mc3R)-null mice suggest the importance of Mc3R-regulated neurons in energy homeostasis, the roles for specific subsets of Mc3R neurons in energy balance have yet to be determined. Because the lateral hypothalamic area (LHA) contributes to the control of energy expenditure and feeding, we generated Mc3rcre mice to determine the roles of LHA Mc3R (Mc3RLHA) neurons in energy homeostasis. We found that Mc3RLHA neurons overlap extensively with LHA neuron markers that contribute to the control of energy balance (neurotensin, galanin, and leptin receptor) and project to brain areas involved in the control of feeding, locomotion, and energy expenditure, consistent with potential roles for Mc3RLHA neurons in these processes. Indeed, selective chemogenetic activation of Mc3RLHA neurons increased locomotor activity and augmented refeeding after a fast. Although the ablation of Mc3RLHA neurons did not alter food intake, mice lacking Mc3RLHA neurons displayed decreased energy expenditure and locomotor activity, along with increased body mass and adiposity. Thus, Mc3R neurons lie within LHA neurocircuitry that modulates locomotor activity and energy expenditure and contribute to energy balance control.


Asunto(s)
Metabolismo Energético , Área Hipotalámica Lateral/fisiología , Receptor de Melanocortina Tipo 3/metabolismo , Adiposidad , Animales , Conducta Alimentaria , Área Hipotalámica Lateral/citología , Locomoción , Ratones , Ratones Transgénicos
5.
Diabetes ; 67(8): 1538-1548, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29776968

RESUMEN

Glucagon-like peptide 1 receptor (GLP-1R) agonists are U.S. Food and Drug Administration-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) affect appetite and body weight are still not fully understood. We determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the short- and long-term effects of the GLP1RA liraglutide on food intake, visceral illness, body weight, and neural network activation. We found that mice lacking GLP-1Rs in vGAT-expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in vGlut2-expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding. Concomitantly, deletion of GLP-1Rs from glutamatergic neurons completely abolished the neural network activation observed after liraglutide administration. We conclude that liraglutide activates a dispersed but discrete neural network to mediate its physiological effects and that these effects require GLP-1R expression on glutamatergic but not GABAergic neurons.


Asunto(s)
Depresores del Apetito/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Hipotálamo/efectos de los fármacos , Liraglutida/uso terapéutico , Neuronas/efectos de los fármacos , Obesidad/tratamiento farmacológico , Animales , Dieta Alta en Grasa/efectos adversos , Ingestión de Energía/efectos de los fármacos , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Genes Reporteros/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/química , Receptor del Péptido 1 Similar al Glucagón/genética , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Proteínas Fluorescentes Verdes/química , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipotálamo/metabolismo , Hipotálamo/patología , Masculino , Ratones Noqueados , Ratones Transgénicos , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/patología , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , Distribución Aleatoria , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/química , Proteína 2 de Transporte Vesicular de Glutamato/genética , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/química , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/genética , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismo , Pérdida de Peso/efectos de los fármacos
6.
Mol Metab ; 3(2): 209-15, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24634830

RESUMEN

Melanocortins and their receptors are critical components of energy homeostasis and the paraventricular nucleus of the hypothalamus (PVH) is an important site of melanocortin action. Although best known for its role in osmoregulation, arginine vasopressin (AVP) has been implicated in feeding and is robustly expressed in the PVH. Since the anorectic melanocortin agonist MTII activates PVH-AVP neurons, we hypothesized that PVH-AVP neurons contribute to PVH-mediated anorexia. To test this, we used an AVP-specific Cre-driver mouse in combination with viral vectors to acutely manipulate PVH-AVP neuron function. Using designer receptors exclusively activated by designer drugs (DREADDs) to control PVH-AVP neuron activity, we show that activation of PVH-AVP neurons acutely inhibits food intake, whereas their inhibition partially reverses melanocortin-induced anorexia. We further show that MTII fails to fully suppress feeding in mice with virally-induced PVH-AVP neuron ablation. Thus PVH-AVP neurons contribute to feeding behaviors, including the acute anorectic response to MTII.

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