The increasing prevalence of obesity represents a growing threat to public health. Challengingly, obesity is a rather treatment-resistant condition and many patients do not obtain the benefits of pharmacological or lifestyle-based interventions. Notably, human genetic studies point to an important role for glutamatergic neurotransmission and neurostructural changes in body weight regulation and obesity pathogenesis. However, this biology is incompletely understood and has yet to undergo pharmacological scrutiny for obesity treatment. In this project proposal the overarching aim is to dissect the importance of the glutamatergic NDMA receptor and its related signaling complex, in physiological and pharmacological regulation of body weight homeostasis. This research holds promise to illuminate a hitherto unknown signaling pathway essential for the regulation of energy homeostasis and to evaluate its druggability for obesity treatment.