Central Action of Brain-Derived Neurotrophic Factor in Male and Female Rats

脑源性神经营养因子在雄性和雌性大鼠中的中枢作用

• 批准号: 8036830
• 负责人: Haifei Shi
• 金额: $ 42.6万
• 依托单位: MIAMI UNIVERSITY OXFORD
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-25 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036830
• 关键词: Central; Action; Brain; Derived; Neurotrophic

DESCRIPTION (provided by applicant): Obesity is a major health problem. A key cause of obesity is increased food intake and decreased energy expenditure. The CNS receives information from the periphery relevant to an individual's energy balance through metabolic, neural, and endocrine signals. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays essential roles in the regulation of energy balance in the CNS by promoting decreased food intake and increased energy expenditure. There is increasing evidence that regulation of energy balance and body weight is not the same for both genders. BDNF neurons are downstream mediators of the melanocortinergic system, and they directly receive input from the proopiomelanocortin (POMC) neurons that are activated by an adiposity signal leptin. Females have greater sensitivity to central leptin than males, suggested by a greater anorexic effect of central leptin administration in females. Thus it is possible that sex difference exists in the leptin-POMC downstream BDNF system. The gender difference in BDNF signaling in energy balance has been suggested from studies using transgenic mice with dysfunctional BDNF system. Decreasing BDNF action by conditionally deleting the BDNF gene or reducing expression of its specific receptor tropomyosin- related kinase B (TrkB) leads to hyperphagia and obesity, with females having more potent phenotypes and developing more severe obesity than males, suggesting that females are more sensitive to the loss of BDNF signaling and thus a functional BDNF system is more crucial in the regulation of energy homeostasis in females. We previously described the phenotype of mice lacking leptin receptors selectively in POMC neurons and identified sex differences in energy balance regulation. Mice with disrupted leptin-POMC signaling exhibit gender-specific physiological mechanisms to reach similar level of obesity; male mice consume more calories while female mice burn fewer calories. The interesting finding is that both males and females with disturbed leptin-POMC signaling show increased adiposity but achieve this through distinct physiological mechanisms. Given these findings we hypothesize that since BDNF system is a direct downstream element of leptin-POMC signaling, the decreased body weight, decreased energy intake, and increased energy expenditure induced by BDNF would be regulated differentially between genders. This R15 proposal aims to elucidate and identify sex differences in the regulation of the BDNF system with the long term goal to generate data that will be useful in developing gender-specific therapeutics to treat or prevent obesity. The effect of BDNF on food intake and energy expenditure has never been thoroughly examined in female rats. Our preliminary data revealed gender-specific effects of central BDNF on food intake and energy expenditure. Males responded with a decreased food intake to a lower centrally injected dose of BDNF than females. Females, but not males, significantly increased their energy expenditure following administration of a low dose of BDNF. These preliminary findings point to very distinct physiological gender-specific mechanisms of body weight regulation. This R15 proposal aims to determine the underlying mechanisms of the sex-specific responses to BDNF treatment. We will first investigate the hypothesis that gonadal hormones modulate the activity of the BDNF/TrkB signaling. We further hypothesize that estrogen enhances the BDNF-induced increase in energy expenditure and that sex differences in energy expenditure may be due to different neural substrates activated by BDNF. By utilizing behavioral, physiological, and molecular techniques, we will examine the relative contributions to feeding and energy expenditure of BDNF and its receptor TrkB in intact and gonadectomized male and female rats using specific TrkB agonist and blocker. The large difference between males and females in the regulation of energy homeostasis suggests the potential need for gender-specific strategies to produce therapeutic weight loss. The role of altered energy intake and expenditure and the underlying mechanism of sex differences in energy homeostasis have not been unequivocally discerned. This R15 proposal will provide important new information about sex differences in response to BDNF treatment. Such information is invaluable for identifying gender- specific biological targets for intervention to prevent or treat obesity. In addition, illuminating how gonadal hormones mediate central BDNF signaling systems to regulate caloric ingestion and energy expenditure will provide critical information on therapeutic targets for postmenopausal women. PUBLIC HEALTH RELEVANCE: As the prevalence of overweight and obesity is rising, the incidence of type 2 diabetes, cardiovascular disease, and some types of cancer is increasing at a similar alarming rate. It is essential that novel therapeutic and prevention strategies for obesity are developed and this can only be achieved by attaining a clear understanding of the factors contributing to energy balance. The CNS receives information from the periphery relevant to an individual's energy balance through metabolic, neural, and endocrine signals. Understanding the neuroendocrine (brain-hormone) control of body weight regulation is critical before specific treatments can be identified. A key cause of obesity is increased food intake and decreased energy expenditure. Brain-derived neurotrophic factor (BDNF) is an essential neuropeptide that plays an integral role in energy balance in the CNS via promoting decreased food intake and increased energy expenditure. There is increasing evidence that the regulation of body weight is not the same for both genders. The role of altered energy intake and expenditure and the underlying mechanism of sex difference in energy homeostasis have not been unequivocally discerned. While it is obvious that differences in gonadal hormones play a key role in regulating differences in body weight between males and females, illuminating how these hormones influence specific biological systems that regulate caloric ingestion and energy expenditure is critical to future therapies. The results obtained from the studies proposed in this R15 proposal will elucidate and identify sex differences in the regulation of the BDNF signaling system with the long term goal to generate data that will be useful in developing gender-specific therapeutics to treat or prevent obesity.

描述（由申请人提供）：肥胖是一个主要的健康问题。肥胖的一个主要原因是食物摄入增加而能量消耗减少。中枢神经系统通过代谢、神经和内分泌信号从外周接收与个体能量平衡相关的信息。脑源性神经营养因子（BDNF）是一种神经营养因子，通过促进食物摄入减少和能量消耗增加，在中枢神经系统的能量平衡调节中起重要作用。越来越多的证据表明，男女对能量平衡和体重的调节是不一样的。BDNF神经元是黑素皮质能系统的下游介质，它们直接接受由肥胖信号瘦素激活的proopiomelanocortin （POMC）神经元输入。女性对中枢瘦素比男性更敏感，这表明在女性中使用中枢瘦素有更大的厌食效果。因此，瘦素- pomc下游BDNF系统可能存在性别差异。利用BDNF系统功能失调的转基因小鼠进行的研究表明，能量平衡中BDNF信号的性别差异。通过有条件地删除BDNF基因或降低其特异性受体原肌球蛋白相关激酶B （TrkB）的表达来降低BDNF的作用，导致暴饮暴食和肥胖，雌性比雄性具有更强的表型和更严重的肥胖，这表明雌性对BDNF信号的丢失更敏感，因此功能性BDNF系统在调节雌性能量稳态中更为重要。我们之前描述了POMC神经元中选择性缺乏瘦素受体的小鼠的表型，并确定了能量平衡调节的性别差异。瘦素- pomc信号被破坏的小鼠表现出性别特异性的生理机制，达到相似的肥胖水平；雄性老鼠消耗更多的卡路里，而雌性老鼠消耗更少的卡路里。有趣的发现是，瘦素- pomc信号紊乱的男性和女性都表现出肥胖增加，但这是通过不同的生理机制实现的。鉴于这些发现，我们假设BDNF系统是瘦素- pomc信号的直接下游元件，BDNF引起的体重下降、能量摄入减少和能量消耗增加的调节在性别之间存在差异。这项R15提案旨在阐明和识别BDNF系统调节中的性别差异，其长期目标是产生数据，这将有助于开发针对性别的治疗方法来治疗或预防肥胖。BDNF对雌性大鼠食物摄入和能量消耗的影响从未被彻底研究过。我们的初步数据揭示了中枢BDNF对食物摄入和能量消耗的性别特异性影响。与雌性相比，雄性对较低的BDNF中央注射剂量的食物摄入量有所减少。在给予低剂量BDNF后，雌性而非雄性的能量消耗显著增加。这些初步发现指出了非常明显的生理性别体重调节机制。本R15提案旨在确定BDNF治疗的性别特异性反应的潜在机制。我们将首先研究性激素调节BDNF/TrkB信号活性的假设。我们进一步假设，雌激素增强了BDNF诱导的能量消耗的增加，能量消耗的性别差异可能是由于BDNF激活的不同神经基质。通过使用行为学、生理学和分子技术，我们将使用特异性TrkB激动剂和阻阻剂，在完整和性腺去角质的雄性和雌性大鼠中检测BDNF及其受体TrkB对摄食和能量消耗的相对贡献。男性和女性在能量平衡调节方面的巨大差异表明，可能需要针对性别的治疗性减肥策略。能量摄入和消耗改变的作用以及能量稳态中性别差异的潜在机制尚未明确。这一R15提案将为BDNF治疗的性别差异提供重要的新信息。这些信息对于确定性别特异性的生物靶点来预防或治疗肥胖是非常宝贵的。此外，阐明性腺激素如何调节中枢BDNF信号系统来调节热量摄入和能量消耗将为绝经后妇女的治疗靶点提供重要信息。