- It remains unclear whether intermuscular adipose tissue (IMAT) has any metabolic influence or whether it is merely a marker of abnormalities, as well as what are the effects of specific lifestyle strategies for weight loss on the dynamics of both IMAT and thigh muscle area (TMA). We followed the trajectory of IMAT and TMA during 18-month lifestyle intervention among 278 sedentary participants with abdominal obesity, using magnetic resonance imaging. We measured the resting metabolic rate (RMR) by an indirect calorimeter. Among 273 eligible participants (47.8±9.3 years of age), the mean IMAT was 9.6±4.6 cm(2) Baseline IMAT levels were directly correlated with waist circumference, abdominal sub-depots, C-reactive protein and leptin, and inversely correlated with baseline TMA and creatinine (p<0.05 for all). After 18 months (86.3% adherence), both IMAT [-1.6%] and TMA [-3.3%] significantly decreased (p<0.01 vs. baseline). The changes in both IMAT and TMA were similar across the lifestyle intervention groups and directly corresponded with moderate weight loss (p<0.001). IMAT change did not remain independently associated with decreased abdominal sub-depots or improved cardiometabolic parameters after adjustments for age, sex, and 18-month weight loss. In similar models, 18-month TMA loss remained associated with decreased RMR, decreased activity, and with increased fasting glucose levels and IMAT (p<0.05 for all). Unlike other fat depots, IMAT may not represent a unique or specific adipose tissue, instead largely reflecting body weight change per se. Moderate weight loss induced a significant decrease in thigh muscle area, suggesting the importance of resistance training to accompany weight loss programs.