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

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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.