S772 Hypodermisin: A Novel Biomarker Associated With Obesity Identified Through In Vivo Protein Trafficking

Introduction: Obesity, which currently affects over 40% of the U.S. population, may result from homeostatic dysregulation of metabolic states. The increasing prevalence of such chronic conditions highlights the need for a greater understanding of modulators influencing feeding behavior and energy balance. Interorgan signaling dysfunction from consumption of highly processed diets can overstimulate critical metabolic pathways. Investigating these communication pathways and protein trafficking can provide valuable insight into key markers involved in disease etiology and progression. Specifically, disrupting interactions between the intestine and white adipose tissue (WAT), which plays a central role in regulating systemic metabolism and energy sensing, may contribute to the development of obesity. Uncovering intestinal secreted proteins trafficked to WAT can lead to druggable targets that may attenuate the progression of obesity and related diseases. Methods: A Cre-inducible endogenous biotin ligase (BirA*G3) affinity tracking system was developed and inserted into mice that allows for biotin-tagging intestinally secreted proteins. Proteins trafficked to 20+ organs were captured using streptavidin affinity enrichment. Mass-tag (TMT) quantitative mass spectrometry proteomics was performed, leading to the identification of hundreds of proteins trafficked from the intestinal epithelium, including GLP1/2, SST, REG3, and CCK, to various organs. Fasting time courses were conducted on mice to elucidate the crosstalk between the intestine and WAT. Results: In this study, hypodermisin (HPD) was identified as an intestinally secreted protein and inhibitor of hormone-induced lipolysis. The mechanism of HPD in vitro was further determined as reducing adipocyte lipolysis and promoting adipogenesis. Furthermore, an intestinal-specific HPD knockout (KO) mouse model was developed. HPD KO mice have increased glucose tolerance during fasted states, decreased insulin resistance, and heavier inguinal subcutaneous WAT with high fat diets in comparison to their controls. HPD KO mice may also have significant decreases in crown-like structures, suggesting a role in immune interplay. Conclusion: The role of HPD in obesity has previously not been characterized. This study indicates the multiple effects of HPD on metabolic processes, highlighting its potential role in obesity. Current studies investigating mechanisms of HPD in glucose tolerance and within the immune landscape are underway.