Unraveling the potential of hypothalamic deep brain stimulation for obesity: Impacts on memory, neuroplasticity and brain metabolism in the Zucker rat.

The lateral hypothalamus (LH) plays a key role in regulating energy balance and appetite, making it a potential target for deep brain stimulation (DBS) in treatment-resistant obesity. In this study, we evaluated the short and long-term in vivo effects of continuous LH-DBS over 15 days in a genetic model of obesity: the Zucker rat. We examined changes in body weight, brain glucose metabolism (via positron emission tomography, PET), and memory performance, along with ex vivo neuroplasticity in different hippocampal layers one month post-treatment. Contrary to expectations, continuous LH-DBS did not reduce the weight gain or food intake. While stimulated rats exhibited hippocampal hypermetabolism and enhanced synaptogenesis, these changes did not translate into cognitive improvements. Interestingly, long-term memory benefits were observed in all animals that underwent surgery, regardless of whether they received stimulation. In conclusion, our results do not support continuous LH-DBS as an effective treatment to reduce body weight in cases of obesity with genetic leptin resistance. However, the hippocampal modulation induced by continuous LH-DBS shows potential for addressing cognitive impairments associated with leptin resistance. These findings suggest that alternative DBS protocols may help restore hippocampal function, warranting further investigation.