Hindbrain catecholamine neurons and body fat

描述(申请人提供)：瘦素是一种脂肪衍生的激素，现在以其减少食物摄入量和体重的能力而闻名。然而，在慢性瘦素治疗期间，食物摄入量最初被抑制，但随后恢复到正常或接近正常水平，尽管瘦素S继续抑制体重增加。这项提议探索了这种感觉恢复的潜在基础机制。最重要的假设是，在慢性瘦素治疗期间，食物摄入量恢复正常，这是由于代谢驱动的消化控制的作用，这些控制不受瘦素诱导的抑制。我们特别测试了这一假设，即在慢性瘦素治疗期间，后脑儿茶酚胺神经元是恢复食物摄入量的重要因素。这些神经元的亚群对摄食具有强大的刺激作用，对脂肪、葡萄糖和蛋白质动员具有广泛的作用，这些都是有效防御葡萄糖代谢所必需的。尽管儿茶酚胺神经元在急性糖耐量低减时糖代谢中的重要作用已被明确，但在长期改变的代谢状态下，后脑儿茶酚胺神经元对食欲和能量平衡的贡献尚未被研究。我们知道，这些儿茶酚胺神经元对摄食的刺激不会被瘦素抑制，它们具有神经联系，可能使它们超越瘦素S对摄食的抑制作用。为了验证我们的假设，我们开发了一个慢性中枢瘦素治疗模型，在该模型中，我们仔细定义了食物摄入量与身体脂肪储存状态的变化。这个模型允许我们定义4种不同的代谢状态。除了为瘦素治疗期间行为和神经元活动的变化提供一致的参考外，该模型还提供了一个健康的、正常食欲但不肥胖的大鼠，这为理解摄食和能量平衡的多种代谢控制的相互作用提供了一个新的视角。特定目标1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。我们研究了在慢性瘦素治疗期间恢复摄食的可能性，可能与后脑儿茶酚胺神经元对无脂肪状态的反应有关。具体目标2将研究在慢性中枢性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将试图通过静脉注射大量营养素来阻止慢性瘦素治疗期间摄食的恢复，类似于之前的工作表明，在应对药物诱导的急性代谢燃料缺乏时，阻断摄食是有效的。体内脂肪储备的状态可能会改变后脑儿茶酚胺神经元的糖调节功能，这对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着关键的糖调节反应，并对无意中的低血糖发作的生存至关重要。公共卫生相关性后脑儿茶酚胺神经元已被证明对葡萄糖稳态和诱导保护大脑免受葡萄糖缺乏症影响的各种反应是必不可少的。在这项提案中，我们将确定这些神经元的活动如何因慢性瘦素治疗导致的体脂消耗而改变。了解体内脂肪储备的状态如何影响糖调节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.