RESUMO
The major female ovarian hormone, 17ß-estradiol (E2), can alter neuronal excitability within milliseconds to regulate a variety of physiological processes. Estrogen receptor-α (ERα), classically known as a nuclear receptor, exists as a membrane-bound receptor to mediate this rapid action of E2, but the ionic mechanisms remain unclear. Here, we show that a membrane channel protein, chloride intracellular channel protein-1 (Clic1), can physically interact with ERα with a preference to the membrane-bound ERα. Clic1-mediated currents can be enhanced by E2 and reduced by its depletion. In addition, Clic1 currents are required to mediate the E2-induced rapid excitations in multiple brain ERα populations. Further, genetic disruption of Clic1 in hypothalamic ERα neurons blunts the regulations of E2 on female body weight balance. In conclusion, we identified the Clic1 chloride channel as a key mediator for E2-induced rapid neuronal excitation, which may have a broad impact on multiple neurobiological processes regulated by E2.
Assuntos
Canais de Cloreto , Receptor alfa de Estrogênio , Neurônios , Neurônios/metabolismo , Canais de Cloreto/metabolismo , Canais de Cloreto/genética , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Animais , Feminino , Humanos , Estradiol/metabolismo , Estradiol/farmacologia , Camundongos , Hipotálamo/metabolismo , Hipotálamo/citologia , Ligação ProteicaRESUMO
Feeding behaviour is influenced by two primary factors: homoeostatic needs driven by hunger and hedonic desires for pleasure even in the absence of hunger. While efficient homoeostatic feeding is vital for survival, excessive hedonic feeding can lead to adverse consequences such as obesity and metabolic dysregulations. However, the neurobiological mechanisms that orchestrate homoeostatic versus hedonic food consumption remain largely unknown. Here we show that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBB) of male mice respond to food presentation. We further demonstrate that a subset of DBBPenk neurons that project to the paraventricular nucleus of the hypothalamus are preferentially activated upon food presentation during fasting periods and transmit a positive valence to facilitate feeding. On the other hand, a separate subset of DBBPenk neurons that project to the lateral hypothalamus are preferentially activated when detecting a high-fat high-sugar (HFHS) diet and transmit a negative valence to inhibit food consumption. Notably, when given free choice of chow and HFHS diets, mice with the whole DBBPenk population ablated exhibit reduced consumption of chow but increased intake of the HFHS diet, resulting in accelerated development of obesity and metabolic disturbances. Together, we identify a molecularly defined neural population in male mice that is crucial for the maintenance of energy balance by facilitating homoeostatic feeding while suppressing hedonic overeating.
Assuntos
Prosencéfalo Basal , Comportamento Alimentar , Animais , Masculino , Camundongos , Comportamento Alimentar/fisiologia , Prosencéfalo Basal/fisiologia , Prosencéfalo Basal/metabolismo , Encefalinas/metabolismo , Ingestão de Alimentos/fisiologia , Precursores de Proteínas/metabolismo , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologia , Obesidade/etiologia , Neurônios/fisiologia , Neurônios/metabolismoRESUMO
Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRNâarcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.
RESUMO
Diabetes classification has traditionally considered type 1 and type 2 diabetes as 2 separate entities with different pathogenic mechanisms. However, clinicians and researchers see increasingly more exceptions to this conventional paradigm, leading to a concept of mixed phenotypes in diabetes classification. Herein we report the case of an adolescent with unclear diabetes type due to the presence of obesity, robust endogenous insulin production, multiple islet autoantibody positivity and severe hyperglycemia at diabetes diagnosis that has been successfully treated with liraglutide therapy alone. Our case report highlights the difficulty of diabetes classification and subsequent need for personalized medicine with regard to diabetes management.
Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Hipoglicemiantes/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeo 1 Semelhante ao Glucagon , Autoanticorpos , Liraglutida/uso terapêutico , InsulinaRESUMO
Despite immense strides in therapeutic advances, clinical outcomes continue to be less than ideal for people with type 1 diabetes. This discrepancy has prompted an outpouring of quality improvement (QI) initiatives to address the medical, psychosocial, and health equity challenges that complicate ideal type 1 diabetes care and outcomes. This article reviews a framework for QI in diabetes care that guided the development of the T1D Exchange Quality Improvement Collaborative to improve care delivery and health outcomes in type 1 diabetes. Evaluation of the methodology, outcomes, and knowledge gained from these initiatives will highlight the importance of continued QI initiatives in diabetes care.