Background: The endogenous factors contributing to long-term changes in body weight are not known but the regulation of energy metabolism by different beta-adrenoceptors (beta(1)-AR, beta(2)-AR, beta(3)-AR) or alpha-adrenoceptors (alpha(2)-AR) may play a role. Methods: In a prospective study, we investigated beta-AR and alpha(2)-AR subtype function in subcutaneous fat cells of 85 healthy, non-obese women by using a standardized bioassay of lipolysis. Of these 73 were re-investigated on an average 10 years later to compare baseline function of beta(1)-AR, beta(2)-AR, beta(3)-AR and alpha(2)-AR with longitudinal weight changes. Results: Weight change over time was normally distributed ranging from -4 kg/m(2) to +6 kg/m(2) in body mass index. Long-term changes in body weight correlated inversely with b3-AR function at base line (r = 0.5, P = 0.001). Those with low beta(3)_AR function gained weight, whereas the opposite was observed with those who had a high b3-AR function. Nineteen percent of weight changes could be explained by beta(3)-AR status. No relationship with weight changes was observed as regards the function of alpha(2)-AR, beta(1)-AR or beta(2)-AR function. Conclusions: beta(3)-ARs are important for long-term changes in body weight putting energy metabolism in adipose tissue in frontline among endogenous factors that regulate body weight in adulthood. International Journal of Obesity (2009) 33, 662-668; doi: 10.1038/ijo.2009.54; published online 14 April 2009