In mammals, critical metabolic and physiological pathways are regulated through dynamic and highly coordinated networks involving tissue cross talk and feedback responses. Nutrient intake, energy expenditure, exercise and exposure to various pathological stressors, are all sensed by highly tuned systems that relay pertinent information to other parts of the body through neural and endocrine cues. Much of these signals come in the form of secreted proteins and metabolites, which act to work locally and systemically to facilitate necessary biological responses. Given the fundamental role of these secreted factors, they represent attractive therapeutic and diagnostic targets in pertinent physiological and disease settings. Accordingly, our group has a strong interest in protein cross talk between metabolic tissues in the setting of obesity and cardiovascular disease. A recent focus of our work has included the role of secreted proteins in driving comorbidities in the setting of heart failure, with a particular interest in proteins that are released by the failing heart that promote pathology in the liver and skeletal muscle. To answer these questions, we have engaged several techniques including temporal proteomic profiling, multi-omic analysis, and TurboID proximity labelling approaches. This presentation will detail our groups experience with these approaches, present some of the findings from this work, and discuss the broader applications of such methodologies.