OBJECTIVE: To determine response rates for clinically significant weight loss (CWL) following different aerobic exercise training amounts and whether enhanced cardiometabolic adaptations are observed with CWL compared to modest weight loss (MWL) or neither. METHODS: Participants (n = 330) performed 6 months of aerobic training at 4 kcal per kilogram per week (KKW), 8 KKW, or 12 KKW (50%, 100%, and 150% of recommended levels respectively). Weight loss was categorized as CWL (> 5%) or MWL (3.0% to 4.9%) or neither. RESULTS: The CWL response rate was greater in the 8 KKW group (20.2%, CI 13.0% to 27.5%) compared to 4 KKW (10.3%, CI 4.6% to 16.0%), but not compared to the 12 KKW group (14.6%, CI 7.6% to 21.6%). Reductions in HOMA-IR were observed in participants with CWL (-0.60, CI -0.98 to -0.22) and with MWL (-0.48, CI -0.87 to -0.10), but not those who achieved neither (-0.06, CI -0.22 to 0.10). No changes between groups were observed for cholesterol, fitness, or blood pressure. CONCLUSIONS: Low response rates for CWL were observed following training, even at levels above recommended levels. Achieving MWL with exercise may represent a reasonable initial weight loss target since the improvement in insulin resistance with MWL is similar to what is achieved with CWL.

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