Hindbrain catecholamine neurons and body fat

后脑儿茶酚胺神经元和身体脂肪

• 批准号: 7858026
• 负责人: W. Sue Ritter
• 金额: $ 30.58万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7858026
• 关键词: Accounting; Acute; Adipose tissue; Adrenal Glands; Anti-Dopamine-b-Hydroxylase Monoclonal Antibody-Saporin; Behavior; Behavioral; Body Weight; Body fat; Brain; Catecholamines; Cerebrum; Chronic; Chronic Phase; Corticosterone; Desire for food; Dopamine; Eating; Emergency Situation; Endocrine; Fatty acid glycerol esters; Glucose; Homeostasis; Hormones; Hypoglycemia; Immunotoxins; Infusion procedures; Intravenous; Leptin; Macronutrients Nutrition; Metabolic; Metabolic Control; Mixed Function Oxygenases; Modeling; Neurons; Obesity; Phase; Proteins; Published Comment; Publishing; Rattus; Recovery; Reporting; Role; Testing; Weight Gain; Work; blood glucose regulation; diabetes management; feeding; hindbrain; neuronal patterning; public health relevance; relating to nervous system; research study; response

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.

描述（由申请人提供）：瘦素是一种脂肪来源的激素，现在以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，最初抑制食物摄入，但尽管瘦素继续抑制体重增加，但随后又恢复到正常水平或接近正常水平。该提案探讨了潜在的收取收费的机制。总体假设是，由于代谢驱动的摄入剂控制的作用，食物的摄入量在慢性瘦素治疗期间恢复正常，而不受瘦素诱导的抑制作用的作用。我们特别检验了后脑儿茶酚胺神经元是慢性瘦素治疗过程中食物摄入量的重要因素的假设。这些神经元的子集对脂肪，葡萄糖和蛋白质动员的饲喂和广泛作用具有有效的刺激作用，这对于有效防御葡萄糖素至关重要。尽管现在明确地在急性葡萄糖急性紧急情况下在急性葡萄糖急性紧急情况下的基本作用是明确的，但尚未研究后脑儿茶酚胺神经元对慢性代谢状态期间食欲和能量稳态的贡献。我们知道，这些儿茶酚胺神经元对喂养的刺激并不能被瘦素抑制，并且它们具有神经连接，可能使它们有可能覆盖瘦素对喂养的抑制作用。为了检验我们的假设，我们开发了一种慢性中央瘦素治疗的模型，在该模型中，我们仔细地定义了食物摄入量相对于人体脂肪储存状态的变化。该模型使我们能够定义4个代谢上不同的代谢状态。除了为瘦素治疗期间的行为和神经元活性变化提供一致的参考外，该模型还提供了一种健康，正常但“无胖”的大鼠，这为理解喂养和能量稳态多种代谢控制的相互作用提供了新的观点。特定目标1中的实验将确定后脑儿茶酚胺神经元对慢性中央瘦素治疗期间行为，代谢和内分泌反应的贡献。我们研究了慢性瘦素治疗期间喂养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。具体目标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中神经元激活中心模式的贡献。特定的目标3将尝试通过静脉内大量营养素输注来阻止慢性瘦素治疗期间的进食，这类似于以前的工作中所显示的那些在响应急性药理学诱导的代谢燃料缺陷而有效阻止进食的喂养。体内脂肪储存的状态可能会改变后脑儿茶酚胺神经元的葡萄糖调节功能对糖尿病及其并发症的治疗具有直接的重要性，因为这些神经元控制了关键的葡萄糖调节反应，并且对无addrect不知所异常的低血糖效果生存至关重要。 公共卫生相关性后脑儿茶酚胺神经元已被证明对于葡萄糖稳态至关重要，并促进了保护大脑免受葡萄糖不足的各种反应。在此提案中，我们将确定这些神经元的活性如何通过慢性瘦素治疗引起的体内脂肪耗竭改变。了解人体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至关重要。