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: 225913899
• 负责人: Professor Dr. Joachim Spranger
• 金额: --
• 依托单位: Institut für Pharmakologie (CCM)
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/225913899?language=en
• 关键词: Hypothalamic; deep; brain; stimulation; novel

A considerable number of patients do not maintain weight loss after lifestyle interventions, despite considerable efforts. Therapeutic opportunities are scarce. We here took a novel interventional approach targeting the link between the activity of dopaminergic brain regions and afferent metabolism control factors, such as leptin. Based on the hypothesis that activation/deactivation of mesolimbic and feed-forward connected regions such as orbitofrontal and dorsolateral cortex are modulated by leptin and may be one of the neural mechanisms contributing to the maintenance of obesity, the team has established stereotactic targeting and deep brain stimulation of the lateral hypothalamus and Nucleus accumbens in mice. Deep brain stimulation (DBS) is a safe, effective and reversible therapy for movement disorders (i.e. approved for essential tremor, Parkinsonus disease and dystonia) and other neuro-psychiatric conditions (e.g. obsessive compulsive disorder). Within the first funding period we developed an experimental setting to continuously stimulate LH and NAc in mice. Our data demonstrate that the stimulation of LH and NAc is feasible and safe in mice and that short-term stimulation does reversibly affect food intake, energy expenditure, locomotor activity and body weight. According to our initial proposal, we also developed and engineered a novel device for bilateral internal DBS in mice, with the opportunity to externally regulate stimulation frequency and amplitude. We are just finishing the ex-vivo testing of this stimulator and will further investigate the device in-vivo within the next months. Independent of the here proposed setting of body weight regulation, we corroborate that the development of such an internal bilateral stimulation device is a substantial step forward for experimental DBS research and may serve numerous other projects in the field of DBS. Using our experimental platform and the newly developed devices, we will aim to further improve our understanding of DBS as a therapeutic approach in morbid obesity. Particularly based on the results of TP6, which further support that the reward value of nutrients predicts body weight maintenance, we will establish an experimental model to analyse rewardassociated phenotypes and behavior analyses in rodents. We will investigate the effects of long-term bilateral internal DBS of the LH, the NAc and, as a novel target, the ventro-medial hypothalamus (VMH). Specifically the internal stimulation approach will offer the opportunity for more detailed metabolic, endocrine and behavior analysis. We will study diet induced models of obesity, but also a monogenic model (i.e. mc4r) considering that patients with monogenic obesity have currently no convincing therapeutic options and may primarily benefit from our yet experimental approach. We will aim to understand the mechanisms of DBS by a joint analysis of endocrine, but also brain and peripheral tissue specimen in collaboration with TP4 (Neuropathology), TP9 (CNS Metabolism), TP1 and TP10 (peripheral tissue metabolism). Notably, we will contribute to the establishment of a joint rodent phenotyping platform at the Charit; to share resources and establish standardized phenotyping procedures in the participating rodent projects. Finally, this project represents a translational research approach. Actually DBS has been established clinically, although the mechanisms beyond its effectiveness are virtually unclear. Assuming encouraging results of our rodent experiments, we will aim to establish DBS as a “Heilversuch” in morbidly obese patients. We envision that patients with unsuccessful bariatric surgery or monogenic obesity might benefit from this novel therapeutic approach.

尽管做出了相当大的努力，但相当多的患者在生活方式干预后并未保持体重减轻。治疗的机会很少。在这里，我们采取了一种新的干预性方法，目标是多巴胺能脑区的活动与传入代谢控制因子之间的联系，如瘦素。基于这样一种假设，即眼眶前额叶和背外侧皮质等中脑边缘和前馈连接区域的激活/去激活受到瘦素的调节，可能是维持肥胖的神经机制之一，该团队已经在小鼠的下丘脑外侧核和伏隔核建立了立体定向靶向和脑深部刺激。脑深部刺激(DBS)是一种安全、有效和可逆的治疗运动障碍(如特发性震颤、帕金森氏病和肌张力障碍)和其他神经精神疾病(如强迫症)的方法。在第一个资助期内，我们开发了一种实验环境来持续刺激小鼠的黄体生成素和NAC。我们的数据表明，在小鼠中刺激促黄体生成素和NAC是可行和安全的，短期刺激确实可逆地影响食物摄入量、能量消耗、运动活动和体重。根据我们的初步建议，我们还开发和设计了一种新的装置，用于小鼠双侧DBS，有机会从外部调节刺激频率和幅度。我们刚刚完成了这个刺激器的体外测试，并将在接下来的几个月内进一步研究这个装置。除了这里提出的体重调节设置之外，我们证实，这种内部双侧刺激装置的开发是DBS实验研究的重要一步，并可能服务于DBS领域的许多其他项目。利用我们的实验平台和新开发的设备，我们将致力于进一步提高我们对DBS作为治疗病态肥胖的方法的理解。特别是，基于TP6的结果，进一步支持营养物质的奖赏价值预测体重维持，我们将建立一个实验模型来分析啮齿动物的奖赏相关表型和行为分析。我们将研究长期双侧内侧背核对黄体生成素、内侧核以及作为新靶点的下丘脑腹内侧核(VMH)的影响。具体地说，内部刺激方法将提供更详细的代谢、内分泌和行为分析的机会。我们将研究饮食诱导的肥胖模型，但也研究单基因肥胖模型(即MC4R)，考虑到单基因肥胖患者目前没有令人信服的治疗选择，可能主要受益于我们尚未进行实验的方法。我们将通过内分泌以及脑和外周组织标本的联合分析，结合TP4(神经病理学)、TP9(中枢神经系统代谢)、TP1和TP10(外周组织代谢)来了解DBS的机制。值得一提的是，我们将促进在Charit建立一个啮齿动物联合表型鉴定平台；在参与的啮齿动物项目中共享资源并建立标准化的表型鉴定程序。最后，这个项目代表了一种翻译研究方法。实际上，DBS已经在临床上建立，尽管其有效性之外的机制几乎还不清楚。假设我们的啮齿动物实验取得了令人鼓舞的结果，我们的目标是在病态肥胖患者中建立DBS作为“海尔维萨奇”。我们设想，减肥手术不成功或单纯性肥胖的患者可能会从这种新的治疗方法中受益。