Project Summary 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. Further, related efforts by our group have positioned us as leaders in characterizing within- and between-tissue molecular responses to exercise and dietary interventions. These experiences, coupled with the high translational relevance of the research problem, motivated our participation in the first phase of the MoTrPAC initiative. Our team was built upon existing collaborations between Duke, Harvard and the Broad Institute with complementary strengths in metabolomics and proteomics technologies and decades of experience in cardiometabolic research. During the initial MoTrPAC funding period, we provided a deep menu of analytical tools for targeted and non-targeted metabolomics, protein profiling, and the analysis of key protein post-translational modifications. Group members were deeply involved in the animal and pre-COVID biochemical profiling efforts, in collaborations with other Chemical Analysis Sites (CAS) and the Bioinformatics Core to harmonize work flows, and in the working groups necessary to integrate the data. We have also played key roles in associated scholarly activities and in developing the next generation of translational investigators focused on exercise science. An additional distinction of our team is the ability to integrate new findings from MoTrPAC with ongoing genomic, proteomic and metabolomic analyses in large human cohorts and other exercise studies led by our investigators. 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 its salutary effects. We are deeply committed to the notion that all data generated by this multi-disciplinary consortium will be made rapidly available to the scientific community. 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 our CAS as one that can have maximal impact on the generation, analysis, and interpretation of molecular profiling data in the next phase of MoTrPAC.

Project Narrative Exercise is an effective intervention for both the prevention and treatment of heart and metabolic diseases. Our goal is to understand the fundamental mechanisms by which exercise confers its healthful benefits. A better understanding of exercise may identify those individuals who are most likely to derive benefit from intensive interventions or novel therapies to improve human health and longevity.