Hindbrain catecholamine neurons and body fat

描述（由申请人提供）：瘦素是一种脂肪源性激素，目前以其减少食物摄入和体重的能力而闻名。然而，在长期瘦素治疗期间，食物摄入最初受到抑制，但随后恢复到正常或接近正常水平，尽管瘦素持续抑制体重增加。这一提议探讨了可能导致这种收费回收的机制。总体假设是，由于代谢驱动的摄食控制的作用，不受瘦素诱导的抑制，在长期瘦素治疗期间食物摄入恢复正常。我们专门测试的假设，后脑儿茶酚胺神经元是重要的贡献者，在慢性瘦素治疗的食物摄入量的恢复。这些神经元的亚群对进食具有强有力的刺激作用，对脂肪、葡萄糖和蛋白质动员具有广泛的作用，这些对于有效防御葡萄糖缺乏是必不可少的。虽然它们在急性葡萄糖缺乏紧急情况下的葡萄糖代谢中的重要作用现在是明确的，但在慢性改变的代谢状态下，后脑儿茶酚胺神经元对食欲和能量稳态的贡献尚未研究。我们知道，这些儿茶酚胺神经元对进食的刺激不受瘦素的抑制，它们拥有的神经连接可能使它们能够克服瘦素对进食的抑制作用。为了验证我们的假设，我们已经开发了一个模型的慢性中枢瘦素治疗中，我们已经仔细定义了食物摄入量的变化与身体脂肪储存的状态。该模型允许我们定义4种代谢上不同的代谢状态。除了为瘦素治疗期间行为和神经元活性的变化提供一致的参考外，该模型还提供了一种健康的、正常进食但“无脂肪”的大鼠，这为理解进食和能量稳态的多种代谢控制的相互作用提供了新的观点。具体目标1中的实验将确定在慢性中枢瘦素治疗期间，后脑儿茶酚胺神经元对行为、代谢和内分泌反应的贡献。我们研究的可能性，在慢性瘦素治疗期间恢复喂养可能与后脑儿茶酚胺神经元的反应，无脂状态。具体目标2将研究在慢性中枢瘦素治疗的不同阶段，后脑儿茶酚胺神经元对神经元激活的中枢模式的贡献。具体目标3将试图通过静脉内大量营养素输注阻断慢性瘦素治疗期间的进食恢复，类似于先前工作中显示的那些有效阻断进食以响应急性药理学诱导的代谢燃料缺陷。身体脂肪储存的状态可能改变后脑儿茶酚胺神经元的葡萄糖调节功能的可能性对于糖尿病及其并发症的管理具有直接的重要性，因为这些神经元控制关键的葡萄糖调节反应，并且对于意外低血糖发作的存活至关重要。 已证明后脑儿茶酚胺神经元对于葡萄糖稳态和引发保护大脑免受葡萄糖缺乏的各种反应是必不可少的。在这个提议中，我们将确定这些神经元的活性是如何通过长期瘦素治疗引起的体脂耗竭而改变的。了解体内脂肪储存的状态如何影响葡萄糖调节性儿茶酚胺神经元的功能，对于糖尿病及其并发症的管理具有重要意义。

DESCRIPTION (provided by applicant): Leptin is an adipose-derived hormone that is now well-known for its ability to reduce food intake and body weight. However, during chronic leptin treatment, food intake is initially suppressed, but then returns to normal or near normal levels despite leptin s continued suppression of body weight gain. This proposal explores mechanisms that potentially underlie this recovery of feeing. The overarching hypothesis is that food intake returns to normal during chronic leptin treatment due to the action of metabolically-driven ingestive controls that are not subject to leptin-induced inhibition. We specifically test the hypothesis that hindbrain catecholamine neurons are important contributors to the recovery of food intake during chronic leptin treatment. Subsets of these neurons have potent stimulatory effects on feeding and widespread actions on fat, glucose and protein mobilization that are essential for effective defense against glucoprivation. Although their essential role in glucorestoration during acute glucoprivic emergency is now unequivocal, the contribution of hindbrain catecholamine neurons to appetite and energy homeostasis during chronically altered metabolic states has not been studied. We know that the stimulation of feeding by these catecholamine neurons is not suppressed by leptin and that they possess neural connections that potentially allow them to override leptin s inhibitory effect on feeding. To test our hypotheses, we have developed a model of chronic central leptin treatment in which we have carefully defined the changes in food intake with respect to the status of body fat stores. This model allows us to define 4 metabolically distinct metabolic states. Besides providing a consistent reference for changes in behavior and neuronal activity during leptin treatment, this model provides a healthy, normophagic but "fatless" rat which provides a new viewpoint for understanding the interaction of multiple metabolic controls of feeding and energy homeostasis. Experiments in Specific Aim 1 will determine the contribution of hindbrain catecholamine neurons to the behavioral, metabolic and endocrine responses during chronic central leptin treatment. We examine the possibility that the recovery of feeding during chronic leptin treatment may be related to the response of hindbrain catecholamine neurons to the fatless state. Specific Aim 2 will examine the contribution of hindbrain catecholamine neurons to central patterns of neuronal activation during different phases of chronic central leptin treatment. Specific Aim 3 will attempt to block the recovery of feeding during chronic leptin treatment by intravenous macronutrient infusions, similar to those shown in previous work to be effective in blocking feeding in response to acute pharmacologically-induced deficits in metabolic fuels. The possibility that the status of body fat stores may alter the glucoregulatory function of hindbrain catecholamine neurons has direct importance for the management of diabetes and its complications, since these neurons control key glucoregulatory responses and are central to survival of inadvertent hypoglycemic bouts. PUBLIC HEALTH RELEVANCE Hindbrain catecholamine neurons have been demonstrated to be essential for glucose homeostasis and for elicitation of a variety of responses that protect the brain against glucose deficit. In this proposal, we will determine how the activity of these neurons is altered by body fat depletion induced by chronic leptin treatment. Understanding how the status of body fat stores influences the function of glucoregulatory catecholamine neurons has importance for management of diabetes and its complications.