Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats

Ari, Csilla; Kovács, Zsolt; Juhász, Gábor; Murdun, Cem; Goldhagen, Craig R.; Koutnik, Andrew P.; Poff, Angela M.; Kesl, Shannon; D’Agostino, Dominic P.

doi:10.3389/fnmol.2016.00137

Cited by 88 publications

(166 citation statements)

References 65 publications

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“…Desrochers and colleagues (10,11) first reported on the esterification of BD and AcAc 2 in 1995 when they showed that the ester provided a convenient way to administer ketones (without sodium load and with the capacity to trap reducing equivalents produced by hepatic BD oxidation) and increase circulating concentrations of AcAc and bHB. BD-AcAc 2 has subsequently been shown to produce beneficial outcomes in rodent models of cognitive dysfunction and neurologic disease (13,14,26). Although the primary outcomes have not focused on energy balance and body weight, multiple studies conducted in mice and rats show that BD-AcAc 2 induces body weight loss with only modest increases in circulating ketones (0.5-1.0 mM) (12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

“…BD-AcAc 2 has subsequently been shown to produce beneficial outcomes in rodent models of cognitive dysfunction and neurologic disease (13,14,26). Although the primary outcomes have not focused on energy balance and body weight, multiple studies conducted in mice and rats show that BD-AcAc 2 induces body weight loss with only modest increases in circulating ketones (0.5-1.0 mM) (12)(13)(14). 3HB-BD has been shown to produce significant increases in circulating ketone concentrations (3.5-7.0 mM) (16,18), but did not produce weight loss, despite higher REE compared to mice receiving matched energy provisions (18).…”

Section: Discussionmentioning

confidence: 99%

“…In response, Brunengraber et al (11) esterified the molecule R,S-1,3-butanediol with diacetoacetate (BD-AcAc 2 ) to overcome this problem and to serve as an alternative to lipid emulsions in parenteral nutrition. Subsequent studies in rodents show that dietary BD-AcAc 2 produces modest increases in circulating ketone concentrations ranging from 0.5 to 1.0 mM and reductions in body weight compared to control animals (12)(13)(14). Despite evidence of reductions in body weight, little is known regarding the effects of BD-AcAc 2 on energy intake and the components of EE.…”

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

et al. 2018

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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‐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

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2018

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“…It has been demonstrated that exogenous ketone (ketogenic) supplements, such as ketone ester (KE), not only increase the level of ketone bodies (e.g., β-hydroxybutyrate/ βHB) [1][2][3][4][5], but also maintain blood levels of ketone bodies in both animals and humans [2,3,6]. Ketone bodies, such as βHB, enter into the brain through blood-brain barrier and provide fuel to brain cells [7,8] improving cell energy metabolism (e.g., enhance mitochondrial ATP synthesis) [9].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, ketone supplement-induced ketosis can suppress neuronal excitability [7,10,11], modulate functions of ion channels and neurotransmitter systems (e.g., increase GABA and adenosine levels) [7,[12][13][14] and influence inflammatory processes (e.g., decrease the concentration and expression of proinflammatory cytokines) [15]. It was suggested that these effects of ketosis may have therapeutic potential in the treatment of several central nervous system (CNS) diseases, such as Alzheimer's disease, Parkinson's disease, epilepsy and psychiatric disorders (e.g., anxiety, schizophrenia and depression) [1,3,8,16]. It was also demonstrated that exogenous ketone supplements, such as KE and ketone salt (KS) are relatively well-tolerated without (or with minimal) adverse effects [1,2,6,16,17].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

et al. 2020

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Background: It has been demonstrated that administration of exogenous ketone supplement ketone salt (KS) and ketone ester (KE) increased blood ketone level and delayed the onset of isoflurane-induced anesthesia in different rodent models, such as Wistar Albino Glaxo Rijswijk (WAG/Rij) rats. The modulatory effect of adenosinergic system may have a role in the ketone supplementation-evoked effects on isoflurane-generated anesthesia. Thus, we investigated whether adenosine receptor antagonists can modulate the effect of exogenous ketone supplements on the onset of akinesia induced by isoflurane. Methods: To investigate the effect of exogenous ketone supplements on anesthetic induction we used ketone supplement KE, KS, KEKS (1:1 mix of KE and KS), KSMCT and KEMCT (1:1 mix of KS and KE with medium chain triglyceride/MCT oil, respectively) in WAG/Rij rats. Animals were fed with standard diet (SD), which was supplemented by oral gavage of different ketone supplements (2.5 g/kg/day) for 1 week. After 7 days, isoflurane (3%) was administered for 5 min and the time until onset of isoflurane-induced anesthesia (time until immobility; light phase of anesthesia: loss of consciousness without movement) was measured. Changes in levels of blood β-hydroxybutyrate (βHB), blood glucose and body weight of animals were also recorded. To investigate the putative effects of adenosine receptors on ketone supplements-evoked influence on isoflurane-induced anesthesia we used a specific adenosine A1 receptor antagonist DPCPX (intraperitoneally/i.p. 0.2 mg/kg) and a selective adenosine A2A receptor antagonist SCH 58261 (i.p. 0.5 mg/kg) alone as well as in combination with KEKS. Results: Significant increases were demonstrated in both blood βHB levels and the number of seconds required before isoflurane-induced anesthesia (immobility) after the final treatment by all exogenous ketone supplements. Moreover, this effect of exogenous ketone supplements positively correlated with blood βHB levels. It was also demonstrated that DPCPX completely abolished the effect of KEKS on isoflurane-induced anesthesia (time until immobility), but not SCH 58261.Conclusions: These findings strengthen our previous suggestion that exogenous ketone supplements may modulate the isoflurane-induced onset of anesthesia (immobility), likely through A1Rs.

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

Deemer

Davis

Roberts

et al. 2020

Obesity

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The aim of this study was to examine the effects of a ketone ester (KE)-supplemented diet on energy expenditure (EE) and adiposity in mice housed at 23 °C versus thermoneutrality (30 °C), in which sympathetic nervous system activity is diminished. Methods: Thirty-two 10-week-old male C57BL/6J mice were assigned to 1 of 4 groups (n = 8 per group): 30% KE diet + 23 °C (KE23), control (CON) diet + 23 °C (CON23), 30% KE diet + 30 °C (KE30), or CON diet + 30 °C (CON30). CON mice were pair-fed to the average intake of mice consuming the KE diet (ad libitum) for 8 weeks. Body composition and components of energy balance were measured at completion of the study. Results: CON23 (mean ± SD, 26.0 ± 1.6 g) and CON30 (29.7 ± 1.4 g) mice weighed more than KE groups (P < 0.03 for both) and were also different from each other (CON23 vs. CON30, P < 0.01). However, KE23 (23.4 ± 2.7 g) and KE30 (23.1 ± 1.9 g) mice were not different in body weight. As expected, food intake at 30 °C (2.0 ± 0.3 g/d) was lower than at 23 °C (2.6 ± 0.3 g/d, P < 0.01). Diet did not influence resting and total EE, but mice housed at 30 °C had lower EE compared with mice at 23 °C (P < 0.01). Conclusions: Dietary KEs attenuate body weight gain at standard (23 °C) and thermoneutral (30 °C) housing temperatures, and this effect is not mediated by increased EE under these conditions.

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Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats

Cited by 88 publications

References 65 publications

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

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

Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

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

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