OBJECTIVE: Obesity results from an imbalance between caloric intake and energy expenditure, which is partly genetically determined. We have investigated, using a PCR-RFLP assay, the effects on weight gain of two genetic variants of the uncoupling proteins and the beta 3-adrenoceptor, two major expressed proteins of the brown adipose tissue (BAT) involved in thermo-genesis. SUBJECTS: 238 morbidly obese and 91 non obese Caucasian subjects. RESULTS: A high prevalence (27%) in French Caucasians of the A-->G change variation located in the 5' flanking domain of the UCP gene was observed with no significant difference between morbidly obese patients and non obese subjects, suggesting that UCP gene is not a major gene for obesity. However, in the population of morbidly obese subjects, the presence of the A-->G allelic variant of the UCP gene showed to be an associated factor of high weight gain during adult life (odd-ratio: 1.4, P = 0.02). Such an association was previously described for the Trp64Arg mutation of the beta 3-AR gene. Furthermore, an additive effect of these two gene variants on weight gain was observed (Odd-Ratio: 4.95, trend test: P = 0.05). The attributable risks for UCP gene and beta 3-AR gene variants were respectively: 25% and 9%. CONCLUSION: These data support the hypothesis of a possible link between energy balance, BAT and weight gain in human.