Brain-derived neurotrophic factor induced weight loss: neural mechanisms

脑源性神经营养因子诱导的体重减轻：神经机制

• 批准号: 7858021
• 负责人: ChuanFeng Wang
• 金额: $ 24.27万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7858021
• 关键词: Affect; Anorexia; Appetite Depressants; Attenuated; Basal metabolic rate; Binding; Body Weight; Body Weight decreased; Brain; Brain-Derived Neurotrophic Factor; Brown Fat; CARTPT gene; Cardiovascular Diseases; Cell Nucleus; Cells; Chemicals; Chronic; Clinical; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Development; Diabetes Mellitus; Diet; Disease; Eating Disorders; Energy Intake; Energy Metabolism; Expenditure; Fatty acid glycerol esters; Health; Injection of therapeutic agent; Knowledge; Laboratories; Leptin; Long-Term Effects; Longevity; Mediating; Neural Pathways; Neuraxis; Neurons; Neuropeptides; Neurotransmitters; Neurotrophic Tyrosine Kinase Receptor Type 2; Newborn Infant; Obesity; Output; Patients; Play; Population; Process; Receptor Signaling; Regulation; Research Personnel; Risk Factors; Role; Series; Signal Pathway; Signal Transduction; Site; Testing; Thermogenesis; Weight Gain; alpha-Melanocyte stimulating hormone; cancer type; combat; energy balance; feeding; mind control; neurogenesis; neuromechanism; neuropeptide Y; neurotrophic factor; newborn neuron; paraventricular nucleus; prevent; public health relevance; receptor-mediated signaling; research study; therapy development; uncoupling protein 1; urocortin

DESCRIPTION (provided by applicant): Obesity is a major health issue. The fundamental problem in obesity is a disordered regulation of energy intake (EI) and/or energy expenditure (EE), which is largely controlled by the brain. Recently, several lines of evidence from our laboratory and others suggest that brain derived neurotrophic factor (BDNF) plays an important role in energy balance. BDNF in the hypothalamic paraventricular nucleus (PVN) and ventromedial nucleus (VMH) shows delayed inhibitory effects on EI and immediate stimulatory effects on EE and resting metabolic rate (RMR). We also found that BDNF immediately increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), suggesting that BDNF induces EE elevation via activation of BAT UCP1. Our preliminary data on potential mechanisms of BDNF effects indicate that: 1) blockade of BDNF binding to TrkB receptor attenuates BDNF-inhibited feeding; 2) blockade of CRH receptor (CRHR) signaling attenuates BDNF-inhibited feeding; and 3) chronic (14 d) injection of BDNF reduces feeding and body weight long-term and increases proliferation of newborn cells in the region. Here we propose 4 hypotheses: 1) BDNF exerts effects on energy metabolism through binding to its receptor TrkB; 2) BDNF effects on energy balance are mediated by CRHR signaling pathway; 3) BDNF prevents high fat diet (HFD) induced obesity; and 4) Chronic BDNF induces proliferation of newborn neurons that impact energy metabolism. The proposal has following 4 specific aims focusing on the VMH site: Aim I. Determine role of BDNF-TrkB signaling in BDNF effects on energy metabolism Does blockade of BDNF-TrkB signaling block BDNF-induced: 1) reduction of feeding and body weight gain, 2) increases in EE, and 3) elevation of UCP1 in BAT? Aim II. Determine role of CRHR signaling in BDNF effects on energy metabolism. Does blockade of CRHR block BDNF-induced: 1) reductions in feeding and body weight, 2) increases in EE, and 3) elevation of UCP1 in BAT? Aim III. Determine effect of BDNF on high fat diet-induced obesity 1) Does chronic BDNF prevent high-fat diet-induced obesity? Aim IV. Determine BDNF effects on neurogenesis and energy metabolism. 1) Does chronic BDNF induce long-term effects on energy balance and neurogenesis? 2) Does blockade of BDNF-induced neurogenesis block BDNF-induced anorexia? 3) Are BDNF-induced newborn neurons responsive to neuropeptides (CRH, leptin, and melanocortin) important to energy metabolism? The proposed studies of BDNF will provide additional information important to our efforts to combat obesity and its associated clinical problems, and thus will benefit a great percentage of obese patients and the public. PUBLIC HEALTH RELEVANCE Obesity is a major health problem affecting a large proportion of the U.S. population, and the fundamental issue of obesity is a regulation disorder of eating and energy output, which is largely controlled by the central nervous system. It is crucial to understand how neural pathways regulate body weight and find approaches to prevent and treat obesity. The proposed studies will determine the process by which a brain chemical, BDNF reduces feeding and increases energy output, which will enable researchers to more informatively focus efforts to combat obesity and its associated clinical problems.

描述（由申请人提供）：肥胖是一个主要的健康问题。肥胖症中的基本问题是对能量摄入（EI）和/或能量消耗（EE）（EE）的调节，主要由大脑控制。最近，我们实验室和其他一些证据表明，脑衍生的神经营养因子（BDNF）在能量平衡中起着重要作用。下丘脑室室内核（PVN）和腹侧核（VMH）中的BDNF显示对EE和静息代谢率（RMR）的抑制作用延迟抑制作用。我们还发现，BDNF立即增加棕色脂肪组织（BAT）中的解偶偶联蛋白1（UCP1）的表达，这表明BDNF通过激活BAT UCP1诱导EE升高。我们有关BDNF效应潜在机制的初步数据表明：1）BDNF与TRKB受体结合的阻断减弱了BDNF抑制的喂养； 2）阻断CRH受体（CRHR）信号传导减弱BDNF抑制的进食； 3）慢性注射BDNF可长期减少喂养和体重，并增加该地区新生细胞的增殖。在这里，我们提出了4个假设：1）BDNF通过与其受体TRKB结合对能量代谢的影响； 2）BDNF对能量平衡的影响由CRHR信号通路介导； 3）BDNF防止高脂饮食（HFD）诱发肥胖； 4）慢性BDNF诱导影响能量代谢的新生神经元的增殖。该提案具有以下4个针对VMH站点的特定目标：AIM I.确定BDNF-TRKB信号在BDNF对能量代谢的影响中的作用确实会阻止BDNF-TRKB信号块BDNF引起的BDNF-TRKB信号块：1）EE的进食和体重的减少，2）EE的降低，以及3）ucp1 in ocp1 in ocp1 in n ocp1 in n ocp1 in n ocp1 in n ocp1。目标II。确定CRHR信号传导在BDNF对能量代谢的影响中的作用。 CRHR阻断BDNF引起的封锁是：1）喂养和体重的减少，2）EE增加； 3）BAT中UCP1的升高？目标三。确定BDNF对高脂饮食诱导的肥胖症的影响1）慢性BDNF是否可以防止高脂饮食诱导的肥胖症？目标IV。确定BDNF对神经发生和能量代谢的影响。 1）慢性BDNF是否诱导对能量平衡和神经发生的长期影响？ 2）封锁BDNF诱导的神经发生阻滞了BDNF诱导的厌食症？ 3）BDNF诱导的新生儿神经元对能量代谢很重要的神经肽（CRH，瘦素和黑色素皮质）有反应吗？拟议的BDNF研究将为我们努力打击肥胖症及其相关临床问题的努力提供其他信息，因此将使肥胖患者和公众受益匪浅。公共卫生相关性肥胖是影响美国大部分人群的主要健康问题，肥胖的基本问题是一种饮食和能量输出的调节障碍，这在很大程度上由中枢神经系统控制。了解神经途径如何调节体重并找到预防和治疗肥胖症是至关重要的。拟议的研究将确定大脑化学物质，BDNF减少喂养并增加能量输出的过程，这将使研究人员能够更加专注地集中精力来打击肥胖及其相关的临床问题。