The ketone bodies (KBs) D-3-hydroxybutyrate (D-3HB) and acetoacetate (AcAc) play a role in starvation and have been associated with insulin resistance. The dose-response relationship between insulin and KBs was demonstrated to be shifted to the right in type 2 diabetes patients. However, KB levels have also been reported to be decreased in obesity. We investigated the metabolic adaptation to fasting with respect to glucose and KB metabolism in lean and obese men without type 2 diabetes using stable glucose and D-3HB isotopes in a two-step pancreatic clamp after 38 h of fasting. We found that D-3HB fluxes in the basal state were higher in lean compared to obese men: 15.2 (10.7-27.1) vs. 7.0 (3.5-15.1) micromol/kg lean body mass (LBM) x min, respectively, P < 0.01. No differences were found in KB fluxes between lean and obese volunteers during the pancreatic clamp (step 1: 6.9 (1.8-12.0) vs. 7.4 (4.2-17.8) micromol/kg LBM x min, respectively; and step 2: 2.9 (0-7.2) vs. 3.4 (0.85-18.7) micromol/kg LBM x min, respectively), despite similar plasma insulin levels. Meanwhile, peripheral glucose uptake was higher in lean compared to obese men (step 1: 15.2 (12.3-25.6) vs. 14.7 (11.9-22.7) micromol/kg LBM x min, respectively, P < or = 0.05; and step 2: 12.5 (7.0-17.3) vs. 10.8 (5.2-15.0) micromol/kg LBM x min, respectively, P < or = 0.01). These data show that obese subjects who display insulin resistance on insulin-mediated peripheral glucose uptake have the same sensitivity for the insulin-mediated suppression of ketogenesis. This implies differential insulin sensitivity of intermediary metabolism in obesity.