RESUMEN
Nonhibernating seasonal mammals have adapted to temporal changes in food availability through behavioral and physiological mechanisms to store food and energy during times of predictable plenty and conserve energy during predicted shortage. Little is known, however, of the hypothalamic neuronal events that lead to a change in behavior or physiology. Here we show for the first time that a shift from long summer-like to short winter-like photoperiod, which induces physiological adaptation to winter in the Siberian hamster, including a body weight decrease of up to 30%, increases neuronal activity in the dorsomedial region of the arcuate nucleus (dmpARC) assessed by electrophysiological patch-clamping recording. Increased neuronal activity in short days is dependent on a photoperiod-driven down-regulation of H3 receptor expression and can be mimicked in long-day dmpARC neurons by the application of the H3 receptor antagonist, clobenproprit. Short-day activation of dmpARC neurons results in increased c-Fos expression. Tract tracing with the trans-synaptic retrograde tracer, pseudorabies virus, delivered into adipose tissue reveals a multisynaptic neuronal sympathetic outflow from dmpARC to white adipose tissue. These data strongly suggest that increased activity of dmpARC neurons, as a consequence of down-regulation of the histamine H3 receptor, contributes to the physiological adaptation of body weight regulation in seasonal photoperiod.
Asunto(s)
Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/efectos de la radiación , Hipotálamo/citología , Fotoperiodo , Receptores Histamínicos H3/metabolismo , Tejido Adiposo Blanco/inervación , Tejido Adiposo Blanco/efectos de la radiación , Animales , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Cricetinae , Electrofisiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Herpesvirus Suido 1/genética , Antagonistas de los Receptores Histamínicos H3/farmacología , Imidazoles/farmacología , Inmunohistoquímica , Hibridación in Situ , Técnicas In Vitro , Masculino , Phodopus , Proteínas Proto-Oncogénicas c-fos/metabolismo , Tiourea/análogos & derivados , Tiourea/farmacologíaRESUMEN
Insulin and leptin receptors are present in hypothalamic regions that control energy homeostasis, and these hormones reduce food intake and body weight in lean, but not obese, Zucker rats. Here we demonstrate that insulin, like leptin, hyperpolarizes lean rat hypothalamic glucose-responsive (GR) neurons by opening KATP channels. These findings suggest hypothalamic K ATP channel function is crucial to physiological regulation of food intake and body weight.
Asunto(s)
Adenosina Trifosfato/farmacología , Hipotálamo/fisiología , Insulina/farmacología , Neuronas/fisiología , Obesidad/fisiopatología , Canales de Potasio/fisiología , Animales , Núcleo Arqueado del Hipotálamo/fisiología , Glucosa/farmacología , Hipotálamo/fisiopatología , Técnicas In Vitro , Leptina/farmacología , Potenciales de la Membrana/efectos de los fármacos , Obesidad/genética , Técnicas de Placa-Clamp , Fosfatidilinositol 3-Quinasas/metabolismo , Canales de Potasio/efectos de los fármacos , Ratas , Ratas Zucker , Delgadez , Tolbutamida/farmacologíaRESUMEN
Leptin, the protein encoded by the obese (ob) gene, is secreted from adipose tissue and is thought to act in the central nervous system to regulate food intake and body weight. It has been proposed that leptin acts in the hypothalamus, the main control centre for satiety and energy expenditure. Mutations in leptin or the receptor isoform (Ob-R[L]) present in hypothalamic neurons result in profound obesity and symptoms of non-insulin-dependent diabetes. Here we show that leptin hyperpolarizes glucose-receptive hypothalamic neurons of lean Sprague-Dawley and Zucker rats, but is ineffective on neurons of obese Zucker (fa/fa) rats. This hyperpolarization is due to the activation of a potassium current, and is not easily recovered on removal of leptin, but is reversed by applying the sulphonylurea, tolbutamide. Single-channel recordings demonstrate that leptin activates an ATP-sensitive potassium (K[ATP]) channel. Our data indicate that the K(ATP) channel may function as the molecular end-point of the pathway following leptin activation of the Ob-R(L) receptor in hypothalamic neurons.