PMI5011 increases fatty acid oxidation and improves skeletal muscle metabolic flexibility, but does not affect the respiratory exchange ratio (RER) or the plasma lipid profile. A) Activity, energy expenditure, and RER were measured by indirect calorimetry at 12 weeks on the HFD alone or supplemented with PMI5011. Least squares means were determined using the data collected over 3 consecutive days. Energy expenditure is normalized to fat-free mass (FFM). Dark bars indicate 7PM–7AM. B) Cholesterol, C) triglycerides, and D) free fatty acids levels were determined at the end of the study. E) Fatty acid oxidation assays were carried out in mixed gastrocnemius muscle homogenates exposed to [1–14C] palmitate ± 10 mm pyruvate. Statistical significance is reported as the mean ± SD, **p < 0.01.