Human obesity can be viewed as a set of phenotypes that evolve over time in a sequence of stages that need to be precisely measured. Environmental, behavioral, genetic and biological factors interact to cause obesity. This presentation provides a clinical viewpoint on some biological processes that may explain some of the stages in the development of human obesity, its chronic maintenance and occurrence of complications, with a focus on brain structures, genetics, the profound alterations in adipose tissue biology and gut microbiota components. Roux-en-Y gastric bypass surgery is an increasingly effective model to study in this context because it leads to major improvements in glucose and lipid homeostasis and to the amelioration of some systemic inflammatory markers.