Hindbrain catecholamine neurons and body fat

描述（由申请人提供）：瘦素是一种脂肪衍生激素，目前以其减少食物摄入和体重的能力而闻名。然而，在慢性瘦素治疗期间，食物摄入量最初受到抑制，但随后恢复到正常或接近正常水平，尽管瘦素继续抑制体重增加。这一建议探讨了潜在的机制，在这种恢复的感觉。总的假设是，在慢性瘦素治疗期间，由于代谢驱动的摄入控制的作用，食物摄入恢复正常，而不受瘦素诱导的抑制。我们特别测试了后脑儿茶酚胺神经元是慢性瘦素治疗期间食物摄入恢复的重要贡献者的假设。这些神经元的亚群对摄食和广泛的脂肪、葡萄糖和蛋白质动员具有强大的刺激作用，这是有效防御葡萄糖活化所必需的。虽然它们在急性葡萄糖中毒紧急情况下的葡萄糖恢复中的重要作用现在已经明确，但在慢性代谢状态改变时，后脑儿茶酚胺神经元对食欲和能量稳态的贡献尚未得到研究。我们知道，这些儿茶酚胺神经元对摄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，在这个模型中，我们仔细定义了食物摄入的变化与身体脂肪储存状态的关系。该模型允许我们定义4种不同的代谢状态。除了为瘦素治疗过程中行为和神经元活动的变化提供一致的参考外，该模型还提供了一只健康、正常饮食但“无脂”的大鼠，为理解摄食和能量稳态多种代谢控制的相互作用提供了新的视角。特异性目的1的实验将确定慢性中枢性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。我们研究慢性瘦素治疗期间进食恢复的可能性可能与后脑儿茶酚胺神经元对无脂状态的反应有关。特异性目标2将检查后脑儿茶酚胺神经元对慢性中枢瘦素治疗不同阶段神经元激活的中枢模式的贡献。特异性Aim 3将尝试通过静脉注射大量营养素来阻断慢性瘦素治疗期间的进食恢复，类似于先前的研究表明，在急性药物诱导的代谢燃料缺陷中，阻断进食是有效的。体脂储存状态可能改变后脑儿茶酚胺神经元的血糖调节功能，这一可能性对糖尿病及其并发症的治疗具有直接意义，因为这些神经元控制着关键的血糖调节反应，对无意中发生的低血糖发作的生存至关重要。后脑儿茶酚胺神经元已被证明对葡萄糖稳态和激发各种保护大脑免受葡萄糖缺乏的反应至关重要。在这个提议中，我们将确定这些神经元的活动如何被慢性瘦素治疗引起的体脂消耗所改变。了解身体脂肪储存状态如何影响血糖调节儿茶酚胺神经元的功能，对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.