RESUMO
Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.
Assuntos
Núcleo Arqueado do Hipotálamo , Receptor alfa de Estrogênio , Comportamento Alimentar , Hidroxicolesteróis , Neurônios , Pró-Opiomelanocortina , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Animais , Hidroxicolesteróis/farmacologia , Hidroxicolesteróis/metabolismo , Receptor alfa de Estrogênio/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Pró-Opiomelanocortina/metabolismo , Camundongos , FemininoRESUMO
Estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HTDRN) to promote binge drinking. We found that female mice drank more alcohol than male mice in chronic drinking in the dark (DID) tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor α (ERα) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling. In supporting this view, 5-HTDRN neurons from naïve male mice had lower baseline firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HTDRN neurons from naïve female mice. Notably, this higher sensitivity was blunted by 17ß-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERα and ERß are expressed in 5-HTDRN neurons, whereas ERα agonist depolarizes and ERß agonist hyperpolarizes 5-HTDRN neurons. Notably, both treatments blocked the stimulatory effects of alcohol on 5-HTDRN neurons in males, even though they have antagonistic effects on the activity dynamics. These results suggest that ERs' inhibitory effects on ethanol-induced burst firing of 5-HTDRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERα- or ERß-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERα/ß to prevent alcohol-induced activation of 5-HTDRN neurons, which in return leads to higher binge alcohol drinking.
Assuntos
Consumo Excessivo de Bebidas Alcoólicas , Receptor alfa de Estrogênio , Camundongos , Feminino , Masculino , Animais , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Serotonina/metabolismo , Estrogênios/farmacologia , Etanol/farmacologiaRESUMO
La enfermedad de Rosai-Dorfman (ERD) es una enfermedad idiopática benigna caracterizada por una proliferación anormal de histiocitos. Desde que fue descripta por Rosai y Dorfman en 1969 son pocos los casos publicados en la literatura, aproximadamente 750 en el mundo. 1- 4La presentación clínica más frecuente son linfadenopatías cervicales bilaterales indoloras. La afectación extranodal ocurre en el 43% de los casos y el compromiso del sistema nervioso central en un 4%.1,3-8 Amos y cols. publican la existencia de 111 casos hasta el año 2008 con afectación del sistema nervioso central (SNC).9 Hasta el año 2011 se han publicado un total de 136 casos.En este artículo presentamos el caso de una paciente con ERD intracraneal sin afectación ganglionar, afectación excepcionalmente rara (únicamente se han publicado 24 casos).
Assuntos
Humanos , Adulto , Feminino , Relatos de Casos , Encefalopatias , Encefalopatias/diagnóstico , Histiocitose Sinusal , Sistema Nervoso Central/anormalidades , Doenças RarasRESUMO
La enfermedad de Rosai-Dorfman (ERD) es una enfermedad idiopática benigna caracterizada por una proliferación anormal de histiocitos. Desde que fue descripta por Rosai y Dorfman en 1969 son pocos los casos publicados en la literatura, aproximadamente 750 en el mundo. 1- 4La presentación clínica más frecuente son linfadenopatías cervicales bilaterales indoloras. La afectación extranodal ocurre en el 43% de los casos y el compromiso del sistema nervioso central en un 4%.1,3-8 Amos y cols. publican la existencia de 111 casos hasta el año 2008 con afectación del sistema nervioso central (SNC).9 Hasta el año 2011 se han publicado un total de 136 casos.En este artículo presentamos el caso de una paciente con ERD intracraneal sin afectación ganglionar, afectación excepcionalmente rara (únicamente se han publicado 24 casos).(AU)