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

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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.