Obesity has reached epidemic proportions throughout much of the industrialized world. Lifestyle and dietary patterns remain critical factors for modulating long term weight control of obese individuals (body mass index, BMI >30), but surgical interventions are often needed to treat morbid obesity (clinically severe, BMI >40). However, the high incidence of bariatric surgery adverse effects and long term complications has kept morbid obesity as an open field for exploration of more effective therapies. Recent studies of appetite regulatory networks, primarily in rodents, have established that targeted electrical stimulation of ventromedial (VMH) and lateral hypothalamic (LHA) circuits can alter orexigenic and anorexigenic signaling through multiple neuronal pathways to modulate feeding patterns. Here we propose to test an innovative and exciting application for electrical brain stimulation as a treatment for morbid obesity. Known as deep brain stimulation (DBS), it has been successfully used to treat various human brain disorders (e.g., Parkinson's disease, epilepsy, cluster headache). Recently, a case report on hypothalamic DBS in a morbidly obese patient described mixed results on its efficacy to produce weight loss, highlighting the need for studies of DBS parameters to achieve desired weight loss without adverse effects. We will develop an animal model of hypothalamic DBS treatment for morbid obesity using G"ttingen minipigs. These animals become naturally obese on unrestricted feeding regimens and represent an excellent human obesity model for preclinical design and evaluation of novel brain interventions. It is essential in this new animal model to first determine the effects of DBS in different hypothalamic targets with different stimulation parameters. As the animals become increasingly obese, we will measure body weight changes due to hypothalamic DBS in VMH vs. LHA with 'stimulatory'low- vs. 'inhibitory'high-frequencies for a 4 month period. We hypothesize that conditions of VMH-low-frequency and LHA-high-frequency will produce reduced weight gain. Plasma levels of glucose, insulin, leptin, and ghrelin will be measured to determine DBS-induced changes in peripheral endocrine markers of food intake and regulation. Brain plasticity will be evaluated in hypothalamus and striatum, post-mortem, based on alterations of dopamine and serotonin receptor subtype densities. This study will demonstrate for the first time in a porcine model the long term efficacy of hypothalamic DBS for modulation of food intake and body weight. The success of this DBS application for obesity control in obesity prone animals will provide experimental evidence for functional CNS effects of electrical stimulation in the hypothalamus, and the scientific justification as well as methodology for using the pig model to explore other brain DBS applications. PUBLIC HEALTH RELEVANCE: This research will develop a pig animal model in which a surgical intervention called deep brain stimulation is evaluated as a treatment for human morbid obesity. Electrical stimulation of the specific brain regions involved in feeding behavior will result in modulation of food intake and body weight. We will show that this intervention method is safe and effective for long term weight control.