Treatment with trimetazidine has no effect on body weight in HFD-induced obese mice but induces a shift in energy substrate metabolism away from fatty acids and toward carbohydrates as an oxidative energy source in vivo. Body weight (A) and glucose intolerance (B) in mice after 10 weeks of high-fat feeding. (C) Body weight of HFD-induced obese mice at 7 days after treatment. Epididymal (D) and perirenal (E) fat pad weight (normalized to body weight) at the time the animals were killed in saline- and trimetazidine-treated HFD-induced obese mice. Plasma TAGs (F) and free fatty acids (FFAs) (G) in the ad libitum state (day 22 after treatment) and fasted state (day 21 after treatment) from HFD-induced obese mice treated with saline or trimetazidine. Respiratory exchange ratio (H—I), whole-body oxygen consumption rates (J), whole-body heat production (K), and locomotor activity (L) in HFD-induced obese mice at days 16–17 after treatment. Values represent mean ± S.E. (n = 5–6). The statistical significance of differences between the two groups was determined by the use of an unpaired, two-tailed Student’s t test. The significance of differences for multiple comparisons was estimated by two-way analysis of variance (ANOVA). When ANOVA revealed differences, multiple t tests with a Bonferroni correction were performed on the data sets. *P < 0.05, statistically significantly different from lean/pre–HFD mice. †P < 0.05, statistically significantly different from saline-treated HFD-induced obese mice.