The second law of thermodynamics asserts that energy within a system must be conserved, and that changes arise from alterations in energy input or output. In obesity, this principle implies that changes in body weight, where energy is stored as triglycerides in adipose tissue, result from alterations in energy intake or expenditure. To maintain a stable body weight, energy intake must balance energy expenditure over time. This theory led to the hypothesis that a hormone derived from adipose tissue could signal the status of energy stores to the brain, which marked a new era in understanding energy balance.

In 1949, researchers at the Jackson Laboratory generated the ob/ob mouse line, which has a spontaneous mutation that causes hyperphagia, severe obesity, hyperglycaemia, hyperinsulinaemia and infertility. Parabiosis experiments revealed that wild-type mice paired with ob/ob mice led to suppressed weight gain, reduced food intake and reduced insulin and glucose levels in the ob/ob mice. These findings suggest that a circulating satiety factor encoded by the ob (now known as Lep) locus from the wild-type partner might signal from adipose tissue to the central nervous system to regulate body weight by modulating food intake and energy expenditure.