In a companion study [Blaak, E.E., M.A. van Baak, G.J. Kemerink, M.T.W. Pakbiers, G.A.K. Heidendal, and W.H.M. Saris. Am. J. Physiol. 267 (Endocrinol. Metab. 30): E306-E315, 1994.], we found that during infusion of the nonselective beta-agonist isoprenaline (Iso), obese males had a lowered Iso-induced rise in arterial glycerol and nonesterified fatty acids (NEFA) and a lowered muscle NEFA oxidation. The present study was intended to investigate whether a period of weight reduction would alter this impaired fat utilization in obese males. Before and after a 5-wk diet intervention (very low calorie diet) whole body energy expenditure was determined during rest and during intravenous infusion of increasing doses of Iso. In addition, forearm muscle metabolism was investigated with Iso infusion with and without simultaneous infusion of the beta 1-blocker atenolol (AT) by measuring skeletal muscle blood flow and arteriovenous concentration differences of various metabolites across muscle. The Iso-induced whole body thermogenesis tended to increase as a result of weight loss when this response was related to the plasma Iso concentration (P = 0.09), whereas both before and after diet there were no changes in the respiratory exchange ratio during Iso infusion. The increases in arterial NEFA and glycerol concentrations as a result of Iso infusion were not significantly different before and after weight reduction. In addition, muscle NEFA uptake did not change as a result of Iso or Iso plus AT infusion both before and after diet, whereas muscle glucose uptake and lactate release tended to be more pronounced after weight reduction.(ABSTRACT TRUNCATED AT 250 WORDS)