Unique and overlapping functions and CNS sites of action for NK2R and LepR signaling

Metabolic diseases such as obesity and diabetes rank among the primary causes of mortality worldwide. While new incretin-based drugs have made major inroads into the treatment of these diseases, issues with tolerance (including nausea, vomiting, diarrhea; and gastroparesis leading to delayed gastric emptying) threaten to limit the potential long-term compliance and impact of these medications. Thus, it is highly relevant to identify therapeutic targets that reduce appetite without activating aversive circuits or promoting gastroparesis. Recently, we discovered Neurokinin 2 Receptor (NK2R) as a new pharmacological target for treating obesity. When activated, NK2R improves energy homeostasis by reducing feeding and increasing energy expenditure, resulting in a decrease in body weight via diminished adiposity. Importantly, NK2R agonism controls appetite without activating CNS circuits that induce aversive effects and, unlike incretin-based therapies, can compensate for leptin-controlled feeding in leptin-deficient hyperphagic mice. This suggests that NK2R agonism mimics leptin for the control of feeding and likely engages leptin-regulated neural circuits. During this fellowship, I will define unique and overlapping functions and CNS sites of action for NK2R and Leptin Receptor signaling using proprietary pharmacological NK2R agonists, molecular genetic neuroscience techniques, metabolic phenotyping, and transcriptomics. This will not only expand our understanding of the promising mode-of-action of NK2R agonists but also has the potential to reveal new mechanisms of central homeostatic control that can be exploited pharmacologically for the treatment of cardiometabolic diseases. The combination of the expertise of my host labs and my experience will ensure the successful completion of the fellowship and uniquely positions me as an expert in both peripheral and central control of energy homeostasis and strengthens my transferable skills to start my independent career.