In search for an approach to identify physiological targets for therapeutic intervention in obesity management, we have revisited the classic human overfeeding studies of the 1960s, with new emphasis on a 'subgroup' of volunteers who were shifted between overfeeding on a typical affluent (normal-protein) diet and overfeeding on a low-protein diet. Following a re-analysis of these data, the arguments are put forward that since low-protein overfeeding is not only a potent stimulus of thermogenesis, but also an amplifier (or magnifier) of the small inter-individual variations in thermogenesis on the affluent (normal-protein) diet, it can be used as a tool to unmask some of the genetic and metabolic basis underlying human susceptibility to leanness and fatness.