Decoding Bariatric Surgery Outcomes through Activity and Transcriptional Analysis of Melanocortin Neurons

PROJECT SUMMARY Bariatric surgeries, such as Vertical Sleeve Gastrectomy (VSG) and Roux-en-Y Gastric Bypass (RYGB), are highly effective interventions for obesity and related metabolic disorders. While they lead to weight loss and improved glucose metabolism, the neural mechanisms underlying these effects are not fully understood. These data suggest disparate and spatially distinct activity profiles of arcuate Neuropeptide Y/Agouti-related Peptide (NPY/AgRP), Proopiomelanocortin (POMC), and leptin receptor (LepR) expressing neurons that may contribute to the metabolic benefits of RYGB and/or VSG. A critical question is whether the changes in arcuate neuron activity precede or are required for the observed metabolic benefits of bariatric surgery. To address this, we will employ electrophysiological techniques to study alterations in neuronal excitability and synaptic physiology, providing insights into the activity patterns of these neurons before the weight loss effects are observed post- bariatric surgery. Additionally, we will measure metabolic parameters while silencing or inhibiting the activity of arcuate POMC, NPY/AgRP, and LepR to investigate if these neurons contribute to the RYGB and/or VSG- induced metabolic benefits. Furthermore, we aim to explore molecular alterations in the differential responses of POMC, NPY/AgRP, and LepR based on the type of bariatric surgery. In pursuing these research objectives, our study seeks to understand the intricate mechanisms and cell populations involved in the metabolic benefits induced by bariatric surgery. Together these data have the potential to inform the development of targeted therapeutic interventions for obesity and associated metabolic disorders.