Brain-derived neurotrophic factor induced weight loss: neural mechanisms

描述（由申请人提供）：肥胖是一个主要的健康问题。肥胖的根本问题是能量摄入（EI）和/或能量消耗（EE）的调节紊乱，这在很大程度上是由大脑控制的。最近，来自我们实验室和其他人的几条证据表明，脑源性神经营养因子（BDNF）在能量平衡中起着重要作用。下丘脑室旁核（PVN）和腹内侧核（VMH）中的BDNF对EI有延迟抑制作用，对EE和静息代谢率（RMR）有即时刺激作用。我们还发现BDNF会立即增加褐色脂肪组织（BAT）中解偶联蛋白1 （UCP1）的表达，这表明BDNF通过激活BAT UCP1诱导EE升高。我们关于BDNF作用可能机制的初步数据表明：1)阻断BDNF与TrkB受体的结合可减弱BDNF抑制的摄食；2)阻断CRH受体（CRHR）信号会减弱bdnf抑制的摄食；3)长期（14 d）注射BDNF可减少喂养量和体重，并增加该区域新生细胞的增殖。我们提出4种假设：1)BDNF通过与其受体TrkB结合来影响能量代谢；2) BDNF对能量平衡的影响是通过CRHR信号通路介导的；3) BDNF预防高脂肪饮食（HFD）引起的肥胖；4)慢性BDNF诱导新生神经元增殖，影响能量代谢。该提案针对VMH部位有以下4个具体目标：目的1 .确定BDNF- trkb信号在BDNF对能量代谢的影响中的作用阻断BDNF- trkb信号是否会阻断BDNF诱导的：1)摄食减少和体重增加，2)EE增加，3)BAT中UCP1升高？目的二世。确定CRHR信号在BDNF能量代谢中的作用。阻断CRHR是否会阻断bdnf诱导：1)摄食和体重减少，2)EE增加，3)BAT中UCP1升高？第三目标。确定BDNF对高脂饮食性肥胖的影响1)慢性BDNF是否能预防高脂饮食性肥胖？目的四：确定BDNF对神经发生和能量代谢的影响。1)慢性BDNF是否对能量平衡和神经发生有长期影响？2)阻断bdnf诱导的神经发生能否阻断bdnf诱导的厌食症？3) bdnf诱导的新生神经元对对能量代谢重要的神经肽（CRH、瘦素和黑素皮质素）有反应吗？拟议的BDNF研究将为我们努力对抗肥胖及其相关临床问题提供额外的重要信息，从而将使很大比例的肥胖患者和公众受益。肥胖是影响美国大部分人口的主要健康问题，肥胖的根本问题是饮食和能量输出的调节障碍，这在很大程度上是由中枢神经系统控制的。了解神经通路如何调节体重并找到预防和治疗肥胖的方法至关重要。拟议的研究将确定脑化学物质BDNF减少进食和增加能量输出的过程，这将使研究人员能够更有信息地集中精力对抗肥胖及其相关的临床问题。

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.