RESUMEN
The mammalian CNS relies on a constant supply of external glucose for its undisturbed operation. However, neurons can readily switch to using fatty acids and ketones as alternative fuels. Here, we show that oleic acid (OA) excites pro-opiomelanocortin (POMC) neurons by inhibition of ATP-activated potassium (K(ATP)) channels. The involvement of K(ATP) channels is further supported by experiments in SUR1 KO animals. Inhibition of beta-oxidation using carnitine palmitoyltransferase-1 inhibitors blocks OA-induced depolarization. The depolarizing effect of OA is specific because it is not mimicked by octanoic acid. Furthermore, OA does not regulate the excitability of agouti-related peptide neurons. High-fat feeding alters POMC neuron excitability, but not its response to OA. Thus beta-oxidation in POMC neurons may mediate the appetite-suppressing (anorexigenic) effects of OA.
Asunto(s)
Hipotálamo/citología , Neuronas/efectos de los fármacos , Ácido Oléico/farmacología , Proopiomelanocortina/metabolismo , Transportadoras de Casetes de Unión a ATP , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Adenosina Trifosfato/farmacología , Análisis de Varianza , Animales , Biofisica , Diazóxido/farmacología , Grasas de la Dieta/administración & dosificación , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica/métodos , Glucosa/metabolismo , Gliburida/farmacología , Proteínas Fluorescentes Verdes/genética , Hipoglucemiantes/farmacología , Técnicas In Vitro , Ratones , Ratones Transgénicos , Modelos Biológicos , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neuronas/metabolismo , Técnicas de Placa-Clamp/métodos , Bloqueadores de los Canales de Potasio , Canales de Potasio de Rectificación Interna/deficiencia , Canales de Potasio de Rectificación Interna/efectos de los fármacos , Canales de Potasio de Rectificación Interna/fisiología , Proopiomelanocortina/genética , Receptores de Droga/deficiencia , Receptores de SulfonilureasRESUMEN
The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1-/-) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1-/- mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1-/- mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and preproorexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1-/- mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.