The recently described variant of the human beta3-adrenergic receptor (AR) gene located mainly in visceral adipocytes is associated with earlier onset of NIDDM, abdominal obesity, insulin resistance, and an increased capacity to gain weight. We investigated whether lipolysis in human omental adipocytes induced by a potent and selective human beta3-AR agonist (L-755,507) was affected by the Trp64Arg mutation of the beta3-adrenoceptor, using 18 omental fat samples obtained during total hysterectomy. The Trp64Arg mutation was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Arg64 homozygous (n = 4) had a lower median effective concentration (EC50) and lower responsiveness compared with wild-type (n = 8) (EC50: -6.55 +/- 0.21 vs. -7.53 +/- 0.35 log mol/l, P = 0.007; responsiveness: 3.48 +/- 0.32 vs. 5.76 +/- 0.36 micromol x 10(5) cells(-1) x 90 min(-1), P = 0.014, respectively), although there was no difference in lipolysis induced by isoproterenol or CGP12177. Trp64Arg heterozygous (n = 6) also had a significantly lower EC50 and lower responsiveness (EC50: -6.18 +/- 0.09 log mol/l; responsiveness: 4.17 +/- 0.33 micromol x 10(5) cells(-1) x 90 min(-1)). We concluded that the Trp64Arg mutation of the beta3-AR gene is associated with lower lipolytic activities.