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

Deemer, Sarah E.; Davis, Rachel; Roberts, Brandon M.; Smith, Daniel L.; Koutnik, Andrew P.; Poff, Angela M.; D’Agostino, Dominic P.; Plaisance, Eric P.

doi:10.1002/oby.22855

Cited by 11 publications

(16 citation statements)

References 24 publications

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“…We found mice consuming a KE diet remained weight stable, with no changes in FM or LBM, yet the control group increased body weight and fat mass over the course of the study. There were no differences in energy intake between the groups, which agrees with our previous findings in juvenile mice ( 19 ). Interestingly, the KE group displayed a unique skeletal muscle transcriptional and proteomic profile compared to the control group yet had a very similar lipidomic profile.…”

Section: Discussionsupporting

confidence: 92%

“…In human clinical trials, circulating ketones such as β-HB reach levels ranging from 1 to 2 mM/L and up to 5 mM/L ( 6 , 84 , 85 ). Comparatively, we (and others) have shown the ability to induce similar levels of ketones in rodents ( 15 , 17 , 19 , 86 ). Exogenous ketones offer a way to induce ketone production quickly and efficiently in humans without the need for caloric restriction or a KD and have been well-studied in exercise physiology ( 11 , 12 , 87 – 89 ).…”

Section: Discussionsupporting

confidence: 50%

“…Furthermore, when housed in thermoneutral conditions, mice consuming BD-AcAc 2 decreased body weight resulting in lower adiposity. The decrease in body weight observed in KE-fed mice transpired without an increase in REE or TEE ( 19 ). These findings suggest that a diet consisting of 25% BD-AcAc 2 can maintain LBM and induce FM loss in young, healthy male mice, but the underlying mechanisms are still unknown.…”

Section: Introductionmentioning

confidence: 99%

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Effects of an exogenous ketone ester using multi-omics in skeletal muscle of aging C57BL/6J male mice

et al. 2022

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Exogenous ketone ester supplementation provides a means to increase circulating ketone concentrations without the dietary challenges imposed by ketogenic diets. Our group has shown that oral R,S-1,3, butanediol diacetoacetate (BD-AcAc2) consumption results in body weight loss or maintenance with moderate increases in circulating ketones. We have previously shown a diet consisting of 25% BD-AcAc2 can maintain lean body mass (LBM) and induce fat mass (FM) loss in young, healthy male mice, but the underlying mechanisms are still unknown. Therefore, the purpose of this study was to determine if a diet consisting of 25% BD-AcAc2 (ketone ester, KE) would alter body composition, transcriptional regulation, the proteome, and the lipidome of skeletal muscle in aged mice. We hypothesized that the KE group would remain weight stable with improvements in body composition compared to controls, resulting in a healthy aging phenotype. Male C57BL/6J mice (n = 16) were purchased from Jackson Laboratories at 72 weeks of age. After 1 week of acclimation, mice were weighed and randomly assigned to one of two groups (n = 8 per group): control (CON) or KE. A significant group by time interaction was observed for body weight (P < 0.001), with KE fed mice weighing significantly less than CON. FM increased over time in the control group but was unchanged in the KE group. Furthermore, LBM was not different between CON and KE mice despite KE mice weighing less than CON mice. Transcriptional analysis of skeletal muscle identified 6 genes that were significantly higher and 21 genes that were significantly lower in the KE group compared to CON. Lipidomic analysis of skeletal muscle identified no differences between groups for any lipid species, except for fatty acyl chains in triacylglycerol which was 46% lower in the KE group. Proteomics analysis identified 44 proteins that were different between groups, of which 11 were lower and 33 were higher in the KE group compared to CON. In conclusion, 72-week-old male mice consuming the exogenous KE, BD-AcAc2, had lower age-related gains in body weight and FM compared to CON mice. Furthermore, transcriptional and proteomics data suggest a signature in skeletal muscle of KE-treated mice consistent with markers of improved skeletal muscle regeneration, improved electron transport chain utilization, and increased insulin sensitivity.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

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Effects of an exogenous ketone ester using multi-omics in skeletal muscle of aging C57BL/6J male mice

et al. 2022

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“…Animal state of ketosis was evaluated via whole blood D-βHB (Keto-MoJo blood ketone meter; Keto-Mojo, Napa, CA, USA) concentrations 86 . Tail vein puncture was used for blood sample, which was tested on day 0 pre-PPE exposure, and then 1- and 2-weeks following AAA induction.…”

Section: Methodsmentioning

confidence: 99%

Ketosis Prevents Abdominal Aortic Aneurysm Rupture Through CCR2 Downregulation and Enhanced MMP Balance

Sastriques-Dunlop

Elizondo-Benedetto

Arif³

et al. 2023

Preprint

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Abdominal aortic aneurysms (AAAs) are common in aging populations, and AAA rupture is associated with high morbidity and mortality. There is currently no effective medical preventative therapy for AAAs to avoid rupture. It is known that the monocyte chemoattractant protein (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis critically regulates AAA tissue inflammation, matrix-metalloproteinase (MMP) production, and in turn extracellular matrix (ECM) stability. However, therapeutic modulation of the CCR2 axis for AAA disease has so far not been accomplished. Since ketone bodies (KBs) are known to trigger repair mechanisms in response to vascular tissue inflammation, we evaluated whether systemic in vivo ketosis can impact CCR2 signaling, and therefore impact AAA expansion and rupture. To evaluate this, male Sprague-Dawley rats underwent surgical AAA formation using porcine pancreatic elastase (PPE), and received daily ?-aminopropionitrile (BAPN) to promote AAA rupture. Animals with formed AAAs received either a standard diet (SD), ketogenic diet (KD), or exogenous KB supplements (EKB). Animals that received KD and EKB reached a state of ketosis, and had significantly reduced AAA expansion and incidence of rupture. Ketosis also led to significantly reduced CCR2, inflammatory cytokine content, and infiltrating macrophages in AAA tissue. Additionally, animals in ketosis had improved balance in aortic wall matrix-metalloproteinase (MMP), reduced extracellular matrix (ECM) degradation, and higher aortic media Collagen content. This study demonstrates that ketosis plays an important therapeutic role in AAA pathobiology, and provides the impetus for future studies investigating the role of ketosis as a preventative strategy for individuals with AAAs.

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“…First of all, d-3HB was shown to be able to improve the blood lipid profile in obese adults by a reduction in lowdensity lipoprotein (LDL) cholesterol, increase in highdensity lipoprotein (HDL) cholesterol, smaller adipocyte cell volume, and inhibition of lipolysis via a G-protein-coupled receptor (GPCR) which reduced subsequent release of serum lipolytic products (Caminhotto et al 2017). At the cellular level, d-3HB markedly increased mitochondrial uncoupling in brown adipose tissue (BAT) which increased mitochondrial respiration and thermogenesis, thereby results in increased resting energy expenditure (REE) in the obese (Deemer et al 2020;Walton et al 2020). More recently, studies revealed that the anti-inflammatory actions of d-3HB on the NOD-like receptor pyrin-domain containing 3 (NLRP3) inflammasome in obese adults can also prevent obesity and associated cardiometabolic complications such as atherosclerosis (Neudorf et al 2020;Zhang et al 2021).…”

Section: D-3hb and Cardiometabolic Healthmentioning

confidence: 99%

On the nutritional and therapeutic effects of ketone body d-β-hydroxybutyrate

Yao¹,

Lyu³

et al. 2021

Appl Microbiol Biotechnol

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d-β-hydroxybutyrate (d-3HB), a monomer of microbial polyhydroxybutyrate (PHB), is also a natural ketone body produced during carbohydrate deprivation to provide energy to the body cells, heart, and brain. In recent years, increasing evidence demonstrates that d-3HB can induce pleiotropic effects on the human body which are highly beneficial for improving physical and metabolic health. Conventional ketogenic diet (KD) or exogenous ketone salts (KS) and esters (KE) have been used to increase serum d-3HB level. However, strict adaptation to the KD was often associated with poor patient compliance, while the ingestion of KS caused gastrointestinal distresses due to excessive consumption of minerals. As for ingestion of KE, subsequent degradation is required before releasing d-3HB for absorption, making these methods somewhat inferior. This review provides novel insights into a biologically synthesized d-3HB (d-3-hydroxybutyric acid) which can induce a faster increase in plasma d-3HB compared to the use of KD, KS, or KE. It also emphasizes on the most recent applications of d-3HB in different fields, including its use in improving exercise performance and in treating metabolic or age-related diseases. Ketones may become a fourth micro-nutrient that is necessary to the human body along with carbohydrates, proteins, and fats. Indeed, d-3HB being a small molecule with multiple signaling pathways within the body exhibits paramount importance in mitigating metabolic and age-related diseases. Nevertheless, specific dose-response relationships and safety margins of using d-3HB remain to be elucidated with more research. Key points• d-3HB induces pleiotropic effects on physical and metabolic health.• Exogenous ketone supplements are more effective than ketogenic diet.• d-3HB as a ketone supplement has long-term healthy impact.

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

Cited by 11 publications

References 24 publications

Effects of an exogenous ketone ester using multi-omics in skeletal muscle of aging C57BL/6J male mice

Effects of an exogenous ketone ester using multi-omics in skeletal muscle of aging C57BL/6J male mice

Ketosis Prevents Abdominal Aortic Aneurysm Rupture Through CCR2 Downregulation and Enhanced MMP Balance

On the nutritional and therapeutic effects of ketone body d-β-hydroxybutyrate

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