Hypothalamic Deep Brain Stimulation for Morbid Obesity:Development of a Pig Model

描述(申请人提供)：肥胖症在工业化世界的大部分地区已经达到流行的程度。生活方式和饮食模式仍然是调节肥胖者长期体重控制的关键因素(身体质量指数，BMI&GT；30)，但通常需要手术干预来治疗病态肥胖(临床严重，BMI&GT；40)。然而，减肥手术不良反应和长期并发症的高发生率使病态肥胖成为探索更有效治疗方法的一个开放领域。最近对食欲调节网络的研究，主要是在啮齿类动物中，已经建立了靶向电刺激腹内侧(VMH)和下丘脑外侧(LHA)回路，可以通过多个神经元通路改变食欲和厌食信号，从而调节摄食模式。在这里，我们建议测试一种创新的、令人兴奋的脑电刺激应用程序，作为治疗病态肥胖的方法。被称为深部脑刺激(DBS)，它已被成功地用于治疗各种人类大脑疾病(如帕金森氏病、癫痫、丛集性头痛)。最近，一份关于病态肥胖患者下丘脑DBS的病例报告描述了其减肥效果的喜忧参半的结果，突显了研究DBS参数的必要性，以实现预期的减肥而不产生不良影响。我们将利用G“ttingen小型猪建立下丘脑DBS治疗病态肥胖的动物模型。这些动物在无限制的喂养方式下会自然肥胖，并代表了一种优秀的人类肥胖模型，可用于临床前设计和评估新的大脑干预措施。在这个新的动物模型中，关键是首先确定DBS在不同刺激参数下丘脑不同靶点的作用。随着动物变得越来越肥胖，我们将在4个月的时间里测量VMH和LHA中由于下丘脑DBS引起的体重变化，使用低频率的刺激性和高频率的抑制性。我们假设，VMH-低频和LHA-高频的条件将产生减少的体重增加。将测量血糖、胰岛素、瘦素和Ghrelin的水平，以确定DBS诱导的食物摄入和调节的外周内分泌标志物的变化。根据多巴胺和5-羟色胺受体亚型密度的变化，将在死后评估下丘脑和纹状体的大脑可塑性。这项研究将首次在猪模型中证明下丘脑DBS在调节食物摄入量和体重方面的长期有效性。该DBS应用于肥胖倾向动物肥胖控制的成功，将为电刺激对下丘脑中枢神经系统功能的影响提供实验证据，并为利用猪模型探索其他脑DBS应用提供科学依据和方法学。公共卫生相关性：这项研究将开发一种猪动物模型，在该模型中，一种名为脑深部刺激的外科干预措施被评估为治疗人类病态肥胖的一种方法。电刺激涉及摄食行为的特定大脑区域将导致食物摄入量和体重的调节。我们将证明这种干预方法对长期体重控制是安全有效的。

DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions throughout much of the industrialized world. Lifestyle and dietary patterns remain critical factors for modulating long term weight control of obese individuals (body mass index, BMI > 30), but surgical interventions are often needed to treat morbid obesity (clinically severe, BMI > 40). However, the high incidence of bariatric surgery adverse effects and long term complications has kept morbid obesity as an open field for exploration of more effective therapies. Recent studies of appetite regulatory networks, primarily in rodents, have established that targeted electrical stimulation of ventromedial (VMH) and lateral hypothalamic (LHA) circuits can alter orexigenic and anorexigenic signaling through multiple neuronal pathways to modulate feeding patterns. Here we propose to test an innovative and exciting application for electrical brain stimulation as a treatment for morbid obesity. Known as deep brain stimulation (DBS), it has been successfully used to treat various human brain disorders (e.g., Parkinson's disease, epilepsy, cluster headache). Recently, a case report on hypothalamic DBS in a morbidly obese patient described mixed results on its efficacy to produce weight loss, highlighting the need for studies of DBS parameters to achieve desired weight loss without adverse effects. We will develop an animal model of hypothalamic DBS treatment for morbid obesity using G"ttingen minipigs. These animals become naturally obese on unrestricted feeding regimens and represent an excellent human obesity model for preclinical design and evaluation of novel brain interventions. It is essential in this new animal model to first determine the effects of DBS in different hypothalamic targets with different stimulation parameters. As the animals become increasingly obese, we will measure body weight changes due to hypothalamic DBS in VMH vs. LHA with 'stimulatory' low- vs. 'inhibitory' high-frequencies for a 4 month period. We hypothesize that conditions of VMH-low-frequency and LHA-high-frequency will produce reduced weight gain. Plasma levels of glucose, insulin, leptin, and ghrelin will be measured to determine DBS-induced changes in peripheral endocrine markers of food intake and regulation. Brain plasticity will be evaluated in hypothalamus and striatum, post-mortem, based on alterations of dopamine and serotonin receptor subtype densities. This study will demonstrate for the first time in a porcine model the long term efficacy of hypothalamic DBS for modulation of food intake and body weight. The success of this DBS application for obesity control in obesity prone animals will provide experimental evidence for functional CNS effects of electrical stimulation in the hypothalamus, and the scientific justification as well as methodology for using the pig model to explore other brain DBS applications. PUBLIC HEALTH RELEVANCE: This research will develop a pig animal model in which a surgical intervention called deep brain stimulation is evaluated as a treatment for human morbid obesity. Electrical stimulation of the specific brain regions involved in feeding behavior will result in modulation of food intake and body weight. We will show that this intervention method is safe and effective for long term weight control.