PROJECT ABSTRACT It is well established that regular physical activity, including endurance (aerobic) exercise training and resistance exercise training has important effects on the prevention and treatment of numerous chronic diseases. Determining the molecular mechanisms or ?map? of the exercise response has become an important focus of biomedical research. The Molecular Transducers of Physical Exercise in Humans Consortium (MoTrPAC) will define the molecular footprint that underlies the enormously beneficial effects of exercise in humans. This application is for a Preclinical Animal Study Site (PASS). This Investigative team has the potential to play an important role in the design and execution of the MoTrPAC project based on our extensive experience and strong record of collaboration. The aims of Phase 1 are: 1) To provide outstanding intellectual contributions and advice, and work in a highly cooperative and collegial manner with the other members of the Steering Committee, to design the best possible experiments for the PASS studies. 2.) To use the wide variety of expertise in the laboratory to carry out highly controlled and accurate exercise studies and collection of animal tissue and blood samples. For this Phase, the rat has been identified as the animal model that most closely mimics humans and the most feasible to study. An emerging concept in exercise biology is that physical exercise activates tissue-to-tissue communication throughout the organism, and this tissue cross- talk can mediate some of the beneficial effects of exercise on health. The goal of Phase 2 is to carry out mechanistic studies to investigate newly and Consortium-identified circulating molecules involved in exercise- regulated tissue cross-talk, including identification of the function and source of the molecules. Skeletal muscle-derived myokines and adipose tissue-derived adipokines will be studied. The Specific Aims of Phase 2 of this project are: 1) To identify novel exercise-regulated adipokines and myokines based on data generated by MoTrPAC; 2) To determine the physiological targets and functions of candidate myokines and adipokines; 3) To determine if exercise-regulated myokines and adipokines can have beneficial effects on metabolic health in normal and metabolically compromised animals; and 4) To determine if putative exercise-induced myokines and adipokines are secreted from skeletal muscle and adipose tissue. These highly innovative studies will dramatically increase our understanding of the mechanisms by which physical activity improves human health and may provide the basis for future therapeutics to combat many chronic diseases.