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The dietary R-3-hydroxybutyrate-R-1, 3-butanediol monoester increases resting energy expenditure (REE) and markers of brown and white adipose thermogenesis in lean mice. The purpose of this investigation was to determine whether the ketone ester, R, S-1, 3-butanediol diacetoacetate (BD-AcAc 2), increases energy expenditure and markers of adipose tissue thermogenesis in the context of high-fat diet (HFD)–induced obesity. Thirty-five-week–old male C57BL/6J mice were placed on an ad libitum HFD (45% kcal) for 10 wk. The mice were then randomized to 1 of 3 groups (n= 10 per group) for an additional 12 wk: 1) control (Con), continuous HFD, 2) pair-fed (PF) to ketone ester (KE); and 3) KE: HFD+ 30% energy from BD-AcAc 2. Mean energy intake throughout the study was∼ 26% lower in the KE compared to the Con group (8.2±0.5 vs. 11.2±0.7 kcal/d; P< 0.05). Final body weight (26.8±3.6 vs. 34.9±4.8 g …