Hypothalamic deep brain stimulation as a novel experimental and therapeutic approach in the treatment of adiposity

下丘脑深部脑刺激作为治疗肥胖的新型实验和治疗方法

• 批准号: 139920637
• 负责人: Professor Dr. Andreas Kupsch
• 金额: --
• 依托单位: Klinik für Stereotaktische Neurochirurgie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/139920637?language=en
• 关键词: Hypothalamic; deep; brain; stimulation; novel

Hormones and nutrients target hypothalamus and brainstem to regulate food intake and energy expenditure, thereby promoting the maintenance of energy reserves. Within the arcuate nucleus, orexigenic NPY and anorexigenic POMC neurons respond to these stimuli and communicate with lateral hypothalamus (LH) and paraventricular nucleus (PVN) neurons modifying energy homeostasis. Modification of food reward sensations is also mediated via central-nervous structures. Reduced leptin signaling after weight loss increases rewarding properties of food, a process likely to include the Nucleus accumbens (NAc). Bidirectional neuronal projections between LH and NAc, supporting those signals of energy homeostasis, may modulate food reward sensations and vice versa. This offers the opportunity to target those neuronal populations by local interventions. Stereotactic approaches with ablative electrocoagulation experiments have convincingly demonstrated the crucial importance of the integrity of hypothalamic anatomical regions for maintenance of energy balance. Deep brain stimulation (DBS), mimicking these lesion effects, is a safe, effective and (notably) reversible therapy for essential tremor, Parkinson´s disease and dystonia. We now aim to apply this technology to the treatment of adiposity. Focusing on hypothalamic DBS (hDBS) of the LH and NAc within this project, effects of an intermittent overnight external bilateral DBS of those structures will be examined in two different mouse models of adiposity, one with monogenic obesity resulting from a loss of function mutation of the MC4R and a model of diet-induced adiposity. Phenotyping of the animals regarding energy homeostasis, body composition and metabolism will be performed considering safety aspects (body temperature, water homeostasis, circadian rhythms or brain integrity). Since external stimulation is limited to a total stimulation time of 2-8 hours per day, novel implantable microstimulation systems for bilateral DBS in mice will be developed and used for subsequent studies using the same animal models. This will offer the opportunity to analyze long-term effects of a chronic or intermittent stimulation on energy homeostasis and safety aspects. Given the existing wide applications of DBS, it might be a feasible, reversible and pathophysiologically reasonable therapeutic approach to treat morbid or monogenic obesity resulting from loss of function mutations of central signaling molecules such as MC4R or leptin receptor, where endocrine approaches might fail. Apart from the expected scientific significance, this project represents a true translational research approach offering the opportunity to transfer the results within an appropriate time frame to the clinical scenario.

激素和营养物质作用于下丘脑和脑干，调节食物摄入和能量消耗，促进能量储备的维持。在弓形核内，厌氧性NPY和厌氧性POMC神经元对这些刺激作出反应，并与外侧下丘脑（LH）和室旁核（PVN）神经元交流，改变能量稳态。食物奖励感觉的改变也是通过中枢神经结构介导的。减肥后瘦素信号的减少增加了食物的奖励特性，这一过程可能包括伏隔核（NAc）。LH和NAc之间的双向神经元投射，支持这些能量稳态信号，可能调节食物奖励感觉，反之亦然。这为通过局部干预针对这些神经元群提供了机会。立体定向方法与烧蚀电凝实验令人信服地证明了下丘脑解剖区域的完整性对维持能量平衡的至关重要。深部脑刺激（DBS），模拟这些病变效应，是一种安全、有效和（明显）可逆的治疗原发性震颤、帕金森病和肌张力障碍的方法。我们现在的目标是将这项技术应用于肥胖的治疗。本项目以LH和NAc的下丘脑DBS （hDBS）为重点，将在两种不同的肥胖小鼠模型中研究对这些结构进行间歇性夜间外部双侧DBS的影响，一种是由于MC4R功能突变丧失而导致的单基因肥胖，另一种是饮食诱导的肥胖模型。将考虑安全方面（体温、水稳态、昼夜节律或脑完整性）对动物的能量稳态、身体组成和代谢进行表型分析。由于外部刺激限于每天2-8小时的总刺激时间，因此将开发用于小鼠双侧DBS的新型植入式微刺激系统，并使用相同的动物模型用于后续研究。这将为分析慢性或间歇性刺激对能量稳态和安全方面的长期影响提供机会。鉴于DBS的广泛应用，它可能是一种可行的、可逆的、病理生理上合理的治疗方法，用于治疗由MC4R或瘦素受体等中心信号分子功能突变丧失引起的病态或单基因肥胖，而内分泌方法可能失败。除了预期的科学意义之外，该项目代表了一种真正的转化研究方法，提供了在适当的时间框架内将结果转移到临床场景的机会。