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The influence of obesity on muscle integrity is not well understood. The purpose of this study was to quantify structural and molecular changes in the rat vastus lateralis (VL) muscle as a function of a 12‐week obesity induction period and a subsequent adaptation period (additional 16‐weeks). Male Sprague–Dawley rats consumed a high‐fat, high‐sucrose (DIO, n = 40) diet, or a chow control‐diet (n = 14). At 12‐weeks, DIO rats were grouped as prone (DIO‐P, top 33% of weight change) or resistant (DIO‐R, bottom 33%). Animals were euthanized at 12‐ or 28‐weeks on the diet. At sacrifice, body composition was determined and VL muscles were collected. Intramuscular fat, fibrosis, and CD68+ cells were quantified histologically and relevant molecular markers were evaluated using RT‐qPCR. At 12‐ and 28‐weeks post‐obesity induction, DIO‐P rats had more mass and body fat than DIO‐R and chow rats (p < …