Massive overweight is an increasing health problem and underlies several complications which in turn result in premature death. The mechanisms underlying the imbalance between energy intake and energy expenditure, that lead to obesity in humans, are still only partly understood. In rodents, heat generation and the burning of calories by the mitochondrial uncoupling protein 1 (UCP1) are important for metabolic control. However, UCP1 is exclusively expressed in brown fat which is only present in limited amounts in human adults. The recent characterization of two new uncoupling proteins, UCP2 and UCP3, may elucidate potentially important pathways for energy expenditure regulation in man. The aim of this study was to investigate whether obesity is accompanied by aberrations in UCP2 and UCP3 regulation. Expression of these two genes was examined using in situ hybridization in six lean and six obese, but otherwise healthy, men. The UCP2 expression was decreased by 28 % (p = 0.001) in the abdominal muscle of the obese subjects. No differences in UCP3 expression were observed between obese and control subjects, although there was great variation in the expression between subjects. In conclusion, these data suggest an impaired activity of the mitochondrial uncoupling protein UCP2, but probably not UCP3, in obese subjects. This may result in decreased energy expenditure and contribute to the development and maintenance of obesity.