A Biochemical Roadmap of Exercise Signaling

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Project Summary/Abstract Exercise is an effective intervention for both the prevention and treatment of cardiometabolic diseases, but the mechanistic underpinnings of the health benefits of exercise remain incompletely defined. Recent work highlights the importance of inter-organ circuits in mediating healthful exercise responses. We identified β- aminoisobutyric acid (BAIBA) as a novel small molecule “myokine” that increases the expression of brown adipocyte-specific genes in vitro, and improves glucose disposal and decreases weight gain in mice. In humans, plasma BAIBA concentrations are increased with chronic exercise and demonstrate a strong inverse association with metabolic risk factors. Our team has also been a leader in characterizing within-tissue responses to exercise and dietary interventions. These experiences, coupled with the high translational relevance of the research problem, motivate us to take a systems wide approach to studying the health benefits of exercise in humans and animal models. To this end, we have formed a multi-institutional, multi-omics center to engage in collaborative studies under the aegis of the NIH MoTrPAC initiative. Our core builds upon ongoing collaborations between teams at Duke, Harvard and the Broad Institute with complementary strengths in metabolomics and proteomics technologies and decades of experience in cardiometabolic research. The core will provide a deep menu of analytical tools for targeted and non-targeted metabolomics, protein profiling, and the analysis of key protein post-translational modifications. Each of the core components has a track record for handling large sample sets, and is well- poised to analyze the expected tens of thousands of tissue and blood samples generated by a national consortium of investigators studying exercise interventions in animal and human cohorts. An additional distinction of our team is the ability to integrate new findings from MoTrPAC with previously collected genomic, proteomic and metabolomic data from large human cohorts. We hypothesize that integrating the metabolomic and proteomic profiles of human tissues and blood during exercise with genetics and detailed human phenotyping will provide novel insights into the inter-organ circuits and within-organ responses that mediate the salutary effects of exercise. All of the primary data generated by this multi- disciplinary proposal will be made rapidly available to the scientific community via a novel information portal at the Broad Institute. Importantly, all four leaders of this proposed core (Carr, Clish, Gerszten and Newgard) have strong track records in the use of metabolomics and proteomics tools for the identification of novel cardiometabolic regulatory and disease mechanisms. These experiences position this proposed core as one that can have maximal impact on the generation, analysis, and interpretation of molecular profiling data.