What do we know of human fuel use during aerobic exercise and how do we know it?

Aerobic exercise is arguably the most metabolically demanding challenge imposed on the human body. The metabolic adaptations to exercise are complex, involving most tissues, and differing substantially depending on the type, severity, and duration of exercise, as well as extent of prior training. Studies of these metabolic responses have been ongoing for decades, including the active NIH-supported consortium MotrPAC. Most studies have been carried out in model organisms, generally rodents or dogs. However, the metabolism of these model organisms substantially differs from humans. We therefore review here what is known specifically of human metabolism during exercise. For the sake of brevity, we focus on aerobic exercise, without extensive prior training. We review methods used to reach conclusions, highlight the many remaining unknowns, and discuss questions requiring future experimental attention.