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

相当多的患者在生活方式干预后，尽管付出了相当大的努力，但仍不能保持体重减轻。治疗机会很少。我们在这里采取了一种新的介入方法，针对多巴胺能脑区域的活动与传入代谢控制因子（如瘦素）之间的联系。基于瘦素调节中边缘和前馈连接区域如眶额皮质和背外侧皮质的激活/失活可能是维持肥胖的神经机制之一的假设，研究小组建立了小鼠下丘脑外侧和伏隔核的立体定向靶向和深部脑刺激。深部脑刺激（DBS）是一种安全、有效和可逆的运动障碍（即批准用于特发性震颤、帕金森病和肌张力障碍）和其他神经精神疾病（如强迫症）的治疗方法。在第一个资助期内，我们开发了一种持续刺激小鼠LH和NAc的实验环境。我们的数据表明，刺激小鼠LH和NAc是可行和安全的，短期刺激确实可逆地影响食物摄入、能量消耗、运动活动和体重。根据我们最初的建议，我们还开发和设计了一种新的装置，用于小鼠双侧内部DBS，有机会从外部调节刺激频率和幅度。我们刚刚完成了这种刺激器的离体测试，并将在未来几个月内进一步研究这种装置的体内测试。在本文提出的体重调节设置之外，我们证实了这种内部双侧刺激装置的开发是实验性DBS研究的重要一步，并可能为DBS领域的许多其他项目提供服务。利用我们的实验平台和新开发的设备，我们将进一步提高我们对DBS作为病态肥胖治疗方法的理解。特别是基于TP6的结果，进一步支持营养素的奖励值预测体重维持，我们将建立一个实验模型来分析啮齿动物的奖励相关表型和行为分析。我们将研究长期双侧内DBS对LH、NAc和下丘脑腹内侧（VMH）的影响。具体来说，内部刺激方法将为更详细的代谢、内分泌和行为分析提供机会。我们将研究饮食诱导的肥胖模型，但考虑到单基因肥胖患者目前没有令人信服的治疗选择，我们的实验方法可能主要受益，我们也将研究单基因模型（即mc4r）。我们将通过与TP4（神经病理学）、TP9（中枢神经系统代谢）、TP1和TP10（外周组织代谢）合作，对内分泌、脑和外周组织标本进行联合分析，以了解DBS的机制。值得注意的是，我们将在Charit建立一个联合啮齿动物表型平台；在参与的啮齿动物项目中共享资源并建立标准化的表型程序。最后，这个项目代表了一种转化研究方法。实际上，DBS已经在临床上建立，尽管其有效性之外的机制实际上尚不清楚。假设我们的啮齿动物实验结果令人鼓舞，我们将致力于在病态肥胖患者中建立DBS作为“Heilversuch”。我们设想，不成功的减肥手术或单基因肥胖患者可能受益于这种新的治疗方法。

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.