DietaryR, S‐1,3‐butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high‐fat diet

Abstract

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‐AcAc2), 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‐AcAc2. 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; P < 0.001) and fat mass (5.2 ± 1.2 vs. 11.3 ± 4.5 g; P < 0.001) of the KE group was significantly lower than PF, despite being matched for energy provisions. Differences in body weight and adiposity were accompanied by higher REE and total energy expenditure in the KE group compared to PF after adjustment for lean body mass and fat‐mass (P = 0.001 and 0.007, respectively). Coupled or uncoupled mitochondrial respiratory rates in skeletal muscle were not different among groups, but markers of mitochondrial uncoupling and thermogenesis (uncoupling protein‐1, deiodinase‐2, and peroxisome proliferator‐activated receptor y coactivator‐1α) were higher in interscapular brown adipose tissue (BAT) of mice receiving the KE diet. The absence of mitochondrial uncoupling in skeletal muscle and increased markers of mitochondrial uncoupling in BAT suggest that BD‐AcAc2 initiates a transcriptional signature consistent with BAT thermogenesis in the context of HFD‐induced obesity.—Davis, R. A. H., Deemer, S. E., Bergeron, J. M., Little, J. T., Warren, J. L., Fisher, G., Smith, D. L., Jr., Fontaine, K. R., Dickinson, S. L., Allison, D. B., Plaisance, E. P. Dietary R,S‐1,3‐butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high‐fat diet. FASEB J. 33, 2409–2421 (2019). http://www.fasebj.org

Effects of an Exogenous Ketone Supplement on Five‐Kilometer Running Performance

“…Ketone esters are widely considered the most potent exogenous ketone supplement and various agents are starting to enter the commercial market. 1,3-butanediol acetoacetate diester, a ketone ester, has recently been shown to reduce body mass and adiposity in obese mice, supporting the idea that ketones change energy metabolism (Davis et al, 2018). MCTs are naturally occurring in a variety of animal and vegetable fat, but can be consumed in a supplemental form.…”

Exogenous Dietary Ketone Ester Decreases Body Weight and Adiposity in Mice Housed at Thermoneutrality

“…To date, studies conducted in mice with KEs have been performed in standard housing temperatures (22-23 °C), which induces activation of the sympathetic nervous system and increases energy expenditure (EE) by approximately 50% more than in thermoneutral housing conditions (11,12). Mice singly housed at standard temperature are under chronic cold stress, a potent stimulator of nonshivering thermogenesis in BAT, and it is thus difficult to differentiate the previously reported effects of KE feeding on BAT thermogenesis (9,10) from the effects of cold exposure. It is important to determine whether reducing sympathetic outflow to BAT, by housing mice at thermoneutrality, reduces the effect of KEs on the metabolic phenotypes produced at standard temperature.…”

“…Approximately 30 mg of BAT was homogenized in radioimmunoprecipitation assay buffer with protease and phosphatase inhibitors using methods previously described (10). Briefly, protein content from homogenates was quantified by protein assay (DC Protein Assay, Bio-Rad, Hercules, California) using fatty acid-free bovine serum albumin (BSA) standards.…”

Journal of Cachexia, Sarcopenia and Muscle

“…Seemingly contrary to the KDE anti-anorexic effects presented here are the ketone-induced reduction in food intake previously reported. 68,69 This was achieved through the alteration of standard diet palatability and a stepwise integration of KDE to mitigate this confounder in non-diseased animals. Additionally, we demonstrated that the KDE mitigated anorexia in both the CACS and LPS/septic anorexic environments.…”

“…All KDE groups exhibited significant reductions in blood glucose levels, with 30% KDE inducing the greatest reduction in glucose. A second study was initiated to expand upon these findings, as prior work revealed that exogenous administration of ketone bodies may reduce ad libitum food intake 68,69 and confound evaluation of KDE effect on catabolism. To control for this effect, food palatability was increased by incrementally integrating the KDE into the diet (5%/day) over a 7-day period to achieve 30% KDE.…”