In this study we investigated whether fat cell lipolysis could be involved in the aetiology of obesity by comparing non-obese subjects with (Hob) or without (Hnorm) a family trait for overweight. A family history of obesity was present when at least one of the first-degree relatives had body mass index of 27 kg/m² or more. Twenty-seven healthy, drugfree non-obese adult subjects were investigated; 13 were Hob and the remaining 14 were Hnorm. Eleven Hob had at least one obese parent. Isolated fat cells from abdominal subcutaneous adipose tissue were incubated in vitro. Glycerol release (lipolysis index), mRNA levels and enzymatic activity of hormone-sensitive lipase and radioligand binding to beta₁- and beta₂-adrenoceptors were determined. The lipolytic effects of noradrenaline (major endogenous lipolytic agent), isoprenaline (a non-selective beta-adrenoceptor agonist), forskolin (a direct activator of adenylyl cyclase) and dibutyryl cyclic AMP (activating protein kinase and thereby hormone-sensitive lipase) were reduced by about 50% (p from 0.001 to 0.01). The maximum activity of hormone-sensitive lipase was reduced 50% in Hob (p<0.05) and correlated with the lipolytic responsiveness of fat cells in the whole population (r=0.71). However, there was no difference between the groups in steady-state mRNA levels for the enzyme. Beta₁-, beta₂- and alpha₂-adrenoceptor sensitivity as well as beta₁- and beta₂-adrenoceptor numbers were normal in Hob. Fasting plasma insulin was 49.1 and 32.6 pmol/l, respectively in Hob and Hnorm (p=0.01). There was, however, no significant correlation between lipolysis in vitro and plasma insulin. Thus, lipolytic catecholamine resistance in fat cells, at least partly due to impaired function of hormone-sensitive lipase, is an adipocyte abnormality associated with a family tendency to obesity.