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

描述（由申请人提供）：肥胖症已达到流行病的比例，在许多工业化国家。生活方式和饮食模式仍然是调节肥胖个体（身体质量指数，BMI > 30）的长期体重控制的关键因素，但通常需要手术干预来治疗病态肥胖（临床严重，BMI > 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的开放领域。最近的食欲调节网络的研究，主要是在啮齿动物中，已经确定，腹内侧（VMH）和外侧下丘脑（LHA）电路的有针对性的电刺激可以改变食欲和食欲信号通过多个神经元通路调节进食模式。在这里，我们建议测试一个创新的和令人兴奋的应用电脑刺激作为治疗病态肥胖。被称为脑深部电刺激（DBS），它已成功地用于治疗各种人脑疾病（例如，帕金森病、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混合结果，强调了DBS参数研究的必要性，以达到预期的减肥效果，而不会产生不良反应。我们将使用哥廷根小型猪建立下丘脑DBS治疗病态肥胖症的动物模型。这些动物在不受限制的喂养方案下变得自然肥胖，并且代表了用于临床前设计和评价新型脑干预的极好的人类肥胖模型。在这种新的动物模型中，必须首先确定DBS在不同刺激参数下对不同下丘脑目标的影响。随着动物变得越来越肥胖，我们将测量VMH与LHA中下丘脑DBS引起的体重变化，其中“刺激性”低频率与“抑制性”高频率持续4个月。我们假设VMH-低频率和LHA-高频率的条件将产生减少的体重增加。将测量葡萄糖、胰岛素、瘦素和饥饿素的血浆水平，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。基于多巴胺和5-羟色胺受体亚型密度的改变，将在死后在下丘脑和纹状体中评价脑可塑性。本研究将首次在猪模型中证明下丘脑DBS调节摄食量和体重的长期有效性。DBS在肥胖易感动物中控制肥胖的成功应用将为下丘脑电刺激的功能性CNS效应提供实验证据，并为使用猪模型探索其他脑DBS应用提供科学依据和方法。公共卫生相关性：这项研究将开发一种猪动物模型，其中一种称为脑深部电刺激的手术干预被评估为人类病态肥胖的治疗方法。电刺激涉及进食行为的特定脑区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于长期控制体重是安全有效的。

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.