Dietary R, S-1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet.

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 γ 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.

Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth.

Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized "precision diets" that may prevent or delay tumor progression based on an individual's specific oncogenic mutation profile.

Acetoacetic acid induces oxidative stress to inhibit the assembly of very low density lipoprotein in bovine hepatocytes.

Dairy cows with fatty liver or ketosis exhibit hyperketonemia, oxidative stress, and a low rate of very low density lipoprotein (VLDL) assembly, and there may be a potential link among these characteristics. Therefore, the objective of this study was to determine the effect of acetoacetic acid (AcAc) on the assembly of VLDL in cow hepatocytes. Cultured cow hepatocytes were treated with different concentrations of AcAc with or without N-acetylcysteine (NAC, an antioxidant). AcAc treatment decreased the mRNA expression and activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and significantly increased malondialdehyde (MDA) content, indicative of oxidative stress. Furthermore, AcAc treatment significantly down-regulated the mRNA expression of apolipoprotein B100 (ApoB100), apolipoprotein E (ApoE), and low density lipoprotein receptor (LDLR), which thus decreased VLDL assembly and increased triglyceride (TG) accumulation in these bovine hepatocytes. Importantly, NAC relieved AcAc-induced oxidative stress and increased VLDL assembly. In summary, these results suggest that AcAc-induced oxidative stress affects the assembly of VLDL, which increases TG accumulation in bovine hepatocytes.

Anticonvulsant properties of an oral ketone ester in a pentylenetetrazole-model of seizure.

The ketogenic diet is known to have an anti-epileptic effect; in fact it is currently used to treat drug resistant epilepsies. The efficacy of this diet is thought to be correlated to the elevation of blood ketone bodies. Because of problems with compliance to this diet, there is an interest in evaluating alternative pharmacological treatments that can have anti-seizure effects by elevating ketone bodies. In the present experiment, an orally administered synthetic ketone ester (R,S - 1,3-butanediol acetoacetate diester, or BD-AcAc2) was evaluated for its anti-seizure efficacy in a rat model. The threshold for seizure induction with progressive intravenous infusion of pentylenetrazole (PTZ) was evaluated in anesthetized Wistar rats two hours after a single 1 ml intragastric administration of BD-AcAc2 (i.e. 4 g/kg b.w., treated group) or water (control group). After correction for the dose of anesthetic, the results showed that the administration of BD-AcAc2 induced an elevation of the PTZ threshold (140 ± 11 mg/kg for the treated group, 122 ± 6 mg/kg for the control group), along with an increased level of blood ß-hydroxybutyrate (2.7 ± 0.3mM for the treated group, 1.4 ± 0.1mM for the control group). This result suggests that ketone esters may pave the road towards the establishment of a "ketogenic diet in a pill".

The extracellular redox state modulates mitochondrial function, gluconeogenesis, and glycogen synthesis in murine hepatocytes.

Circulating redox state changes, determined by the ratio of reduced/oxidized pairs of different metabolites, have been associated with metabolic diseases. However, the pathogenic contribution of these changes and whether they modulate normal tissue function is unclear. As alterations in hepatic gluconeogenesis and glycogen metabolism are hallmarks that characterize insulin resistance and type 2 diabetes, we tested whether imposed changes in the extracellular redox state could modulate these processes. Thus, primary hepatocytes were treated with different ratios of the following physiological extracellular redox couples: ß-hydroxybutyrate (ßOHB)/acetoacetate (Acoc), reduced glutathione (GSH)/oxidized glutathione (GSSG), and cysteine/cystine. Exposure to a more oxidized ratio via extracellular ßOHB/Acoc, GSH/GSSG, and cysteine/cystine in hepatocytes from fed mice increased intracellular hydrogen peroxide without causing oxidative damage. On the other hand, addition of more reduced ratios of extracellular ßOHB/Acoc led to increased NAD(P)H and maximal mitochondrial respiratory capacity in hepatocytes. Greater ßOHB/Acoc ratios were also associated with decreased ß-oxidation, as expected with enhanced lipogenesis. In hepatocytes from fasted mice, a more extracellular reduced state of ßOHB/Acoc led to increased alanine-stimulated gluconeogenesis and enhanced glycogen synthesis capacity from added glucose. Thus, we demonstrated for the first time that the extracellular redox state regulates the major metabolic functions of the liver and involves changes in intracellular NADH, hydrogen peroxide, and mitochondrial respiration. Because redox state in the blood can be communicated to all metabolically sensitive tissues, this work confirms the hypothesis that circulating redox state may be an important regulator of whole body metabolism and contribute to alterations associated with metabolic diseases.

ß-Phenylethylamine as a novel nutrient treatment to reduce bacterial contamination due to Escherichia coli O157:H7 on beef meat.

Bacterial infection by Escherichia coli O157:H7 through the consumption of beef meat or meat products is an ongoing problem, in part because bacteria develop resistances towards chemicals aimed at killing them. In an approach that uses bacterial nutrients to manipulate bacteria into behaviors or cellular phenotypes less harmful to humans, we screened a library of 95 carbon and 95 nitrogen sources for their effect on E. coli growth, cell division, and biofilm formation. In the initial screening experiment using the Phenotype MicroArray(TM) technology from BioLog (Hayward, CA), we narrowed the 190 starting nutrients down to eight which were consecutively tested as supplements in liquid beef broth medium. Acetoacetic acid (AAA) and ß-phenylethylamine (PEA) performed best in this experiment. On beef meat pieces, PEA reduced the bacterial cell count by 90% after incubation of the PEA treated and E. coli contaminated meat pieces at 10°C for one week.

Neuroprotection by acetoacetate and ß-hydroxybutyrate against NMDA-induced RGC damage in rat--possible involvement of kynurenic acid.

PURPOSE: This study investigated the effects of systemically administered lithium acetoacetate (ACA) and sodium ß-hydroxybutyrate (BHB) in a rat model of N-methyl-D-aspartate (NMDA)-induced damage of retinal ganglion cells (RGC). Additionally, the influence of ACA and BHB on kynurenic acid (KYNA) production was assessed in vitro in bovine retinal slices. METHODS: Female adult Brown-Norway rats in groups of 5-8 animals were used. ACA and BHB were administered intraperitoneally once a day for 21 consecutive days, and phosphate buffered saline (PBS) was administered to control animals. After 2 weeks, the animals received intraocular NMDA (2 µl of a 10 mM solution in PBS) or intraocular PBS as a control. On day 19, retinal ganglion cells were labeled retrogradely with hydroxystilbamidine. Two days later, RGC density (cells per mm(2)) was assessed on retinal flatmounts. Additionaly, bovine retinal slices were incubated with NMDA and ACA or BHB at concentrations of 1.0 mM and 3.0 mM, and de novo KYNA production was measured using HPLC. RESULTS: Intraperitoneal ACA (250 mg/kg) or BHB (291.2 mg/kg) significantly protected RGC against NMDA-induced neurodegeneration. De novo KYNA production in bovine retinal slices was lowered by NMDA. Both ACA and BHB at a concentration of 3.0 mM significantly reduced the effects of NMDA. CONCLUSIONS: ACA and BHB had a significant dose-dependent neuroprotective effect on RGC in a rat model of NMDA-induced RGC damage. Both ketone bodies also significantly attenuated NMDA-induced reduction of retinal KYNA production in vitro, suggesting that this mechanism may be essential for the neuroprotective effects of ACA and BHB in vivo. Our results imply that ketone bodies may represent an additional treatment option in chronic neurodegenerative disorders of the eye.

Physiological and biochemical effects of allelochemical ethyl 2-methyl acetoacetate (EMA) on cyanobacterium Microcystis aeruginosa.

The physiological and biochemical effects of an allelochemical ethyl 2-methyl acetoacetate (EMA) isolated from reed (Phragmites communis) on bloom-forming cyanobacterium, Microcystis aeruginosa, were investigated. EMA significantly inhibited the growth of M. aeruginosa in a concentration-dependent way. The metabolic indices (represented by esterase and total dehydrogenase activities), the cellular redox status (represented by the level of reactive oxygen species (ROS)), and the oxidative damage index (represented by the content of malondialdehyde (MDA), the product of membrane lipid peroxidation) were used to evaluate the physiological and biochemical changes in M. aeruginosa after EMA exposure. Esterase activity in M. aeruginosa did not change (P>0.05) after 2 h of exposure to EMA, but increased greatly after 24 and 48 h (P<0.05). EMA exposure (>0.5 mg L(-1)) resulted in a remarkable loss of total dehydrogenase activity in M. aeruginosa after 4 h (P<0.01), but an increase after 40 h (P<0.05). EMA caused a great increase in ROS level of the algal cells. At high EMA concentration (4 mg L(-1)), the ROS level was remarkably elevated to 1.91 times as much as that in the controls after 2 h. Increases in the ROS level also occurred after 24 and 48 h. The increase in lipid peroxidation of M. aeruginosa was dependent upon EMA concentration and the exposure time. After 40 h of exposure, the MDA content at 4 mg L(-1) of EMA reached approximately 3.5 times (P<0.01) versus the controls. These results suggest that the cellular structure and metabolic activity of M. aeruginosa are influenced by EMA; the increased metabolic activity perhaps reflects the fact that the resistance of cellular response system to the stress from EMA is initiated during EMA exposure, and the oxidative damage induced by EMA via the oxidation of ROS may be an important factor responsible for the inhibition of EMA on the growth of M. aeruginosa.

Effect of enteral nutrition of monoacetoacetin on bacterial translocation in burned rats.

BACKGROUND: Bacterial translocation (BT) occurs under stress, and enteral nutrition is said to be effective in counteracting this effect. The usefulness of i.v. nutrition of monoacetoacetine (MA) under stress has been reported previously, and we studied the effect of enteral nutrition of MA as it is related to BT. METHODS: Rats were given 13.6% MA or 15% glucose (Glu) via gastrostomy, and after 4 days a 30% full-thickness burn was made. Before and after administration of the burn, we measured serum cytokines; amounts of bacteria in the mesenteric lymph node (MLN), liver, and spleen (estimation of BT); mucosal thickness of the terminal ileum; and body weight changes. To confirm the effectiveness of MA in the small intestine, we estimated succinyl-CoA:3-oxoacid CoA-transferase (SCOT) expression in the terminal ileum by immunohistochemical staining and Western blot analysis. RESULTS: At 6 hours after burn, all cytokines were lower, and BT in the MLN was inhibited significantly in the MA group. Ileal mucosal thickness was not significantly different, but mucosa was more edematous in the Glu group. At 3 days after burn injury, BT was significantly inhibited in the MLN and liver, and the ileal mucosa was significantly thicker in the MA group. Body weight loss after burn injury was significantly smaller in the MA group. SCOT expression was the strongest at 6 hours after burn injury by Western blot analysis but not by immunohistochemical staining. CONCLUSIONS: Enteral nutrition of MA may be useful for the inhibition of intestinal mucosal atrophy and the prevention of multiple organ dysfunction syndrome caused by the inhibition of BT and subsequent overproduction of cytokines.

Acetoacetate augments beta-adrenergic inotropism of stunned myocardium by an antioxidant mechanism.

Blunted beta-adrenergic inotropism in stunned myocardium is restored by pharmacological (N-acetylcysteine) and metabolic (pyruvate) antioxidants. The ketone body acetoacetate is a natural myocardial fuel and antioxidant that improves contractile function of prooxidant-injured myocardium. The impact of acetoacetate on postischemic cardiac function and beta-adrenergic signaling has never been reported. To test the hypothesis that acetoacetate restores contractile performance and beta-adrenergic inotropism of stunned myocardium, postischemic Krebs-Henseleit-perfused guinea pig hearts were treated with 5 mM acetoacetate and/or 2 nM isoproterenol at 15-45 and 30-45 min of reperfusion, respectively, while cardiac power was monitored. The myocardium was snap frozen, and its energy state was assessed from phosphocreatine phosphorylation potential. Antioxidant defenses were assessed from GSH/GSSG and NADPH/NADP(+) redox potentials. Stunning lowered cardiac power and GSH redox potential by 90 and 70%, respectively. Given separately, acetoacetate and isoproterenol each increased power and GSH redox potential three- to fivefold. Phosphocreatine potential was 70% higher in acetoacetate- vs. isoproterenol-treated hearts (P < 0.01). In combination, acetoacetate and isoproterenol synergistically increased power and GSH redox potential 16- and 7-fold, respectively, doubled NADPH redox potential, and increased cAMP content 30%. The combination increased cardiac power four- to sixfold vs. the individual treatments without a coincident increase in phosphorylation potential. Potentiation of isoproterenol's inotropic actions endured even after acetoacetate was discontinued and GSH potential waned, indicating that temporary enhancement of redox potential persistently restored beta-adrenergic mechanisms. Thus acetoacetate increased contractile performance and potentiated beta-adrenergic inotropism in stunned myocardium without increasing energy reserves, suggesting its antioxidant character is central to its beneficial actions.

Acetoacetate increases expression of intercellular adhesion molecule-1 (ICAM-1) in human brain microvascular endothelial cells.

It has been hypothesized that ketone bodies cause activation of brain endothelial cells and that this is a factor in the intracerebral crises of diabetic ketoacidosis (DKA). In this study we used cultured human brain microvascular endothelial cells (HBMEC) to investigate the effect of beta hydroxybutyrate (BOHB) and acetoacetate (AcAc) on the expression of the adhesion molecule, intercellular adhesion molecule-1 (ICAM-1). Increasing concentrations of AcAc, but not BOHB, caused a significant upregulation of ICAM-1 in comparison to unstimulated cells. Glucose concentrations of 10 and 30 mM, but not 50 mM, also resulted in increased expression of ICAM-1. These results support the hypothesis that activation of HBMEC is involved in the acute complications of DKA, and that ketone bodies and hyperglycemia are factors in the perturbed membrane function.

Triidothyronine and epinephrine rapidly modify myocardial substrate selection: a (13)C isotopomer analysis.

Triiodothyronine (T(3)) exerts direct action on myocardial oxygen consumption (MVO(2)), although its immediate effects on substrate metabolism have not been elucidated. The hypothesis, that T(3) regulates substrate selection and flux, was tested in isovolumic rat hearts under four conditions: control, T(3) (10 nM), epinephrine (Epi), and T(3) and Epi (TE). Hearts were perfused with [1,3-(13)C]acetoacetic acid (AA, 0.17 mM), L-[3-(13)C]lactic acid (LAC, 1.2 mM), U-(13)C-labeled long-chain free fatty acids (FFA, 0.35 mM), and unlabeled D-glucose (5.5 mM) for 30 min. Fractional acetyl-CoA contribution to the tricarboxylic acid cycle (Fc) per substrate was determined using (13)C NMR and isotopomer analysis. Oxidative fluxes were calculated using Fc, the respiratory quotient, and MVO(2). T(3) increased (P < 0.05) Fc(FFA), decreased Fc(LAC), and increased absolute FFA oxidation from 0.58 +/- 0.03 to 0.68 +/- 0.03 micromol. min(-1). g dry wt(-1) (P < 0.05). Epi decreased Fc(FFA) and Fc(AA), although FFA flux increased from 0.58 +/- 0.03 to 0.75 +/- 0.09 micromol. min(-1). g dry wt(-1). T(3) moderated the change in Fc(FFA) induced by Epi. In summary, T(3) exerts direct action on substrate pathways and enhances FFA selection and oxidation, although the Epi effect dominates at a high work state.

Synthesis and intravenous infusion into the rat of glyceryl bisacetoacetate, 1-acetoacetamido-2, 3-propane diol, and partially reduced glucosyl pentaacetoacetate.

The efficacy of parenteral nutrition could be improved by finding a more effective energy source. Esters of short-chain fatty acids have exhibited some promise as alternatives to glucose. The present study reports on two new esters and one amide, each containing acetoacetate as the organic acid. The three compounds: glyceryl bisacetoacetate, N-2',3'-dihydroxypropyl-3-oxo-butanamide (1-acetoacetamido-2,3-propane diol), and partially reduced glucosyl pentaacetoacetate, were synthesized and then continuously infused into rats for 7 d. The infusion rate provided 50% of the rats' estimated metabolic energy requirements, and rats were fed with a reduced-energy oral diet that provided the remaining 50% of energy plus adequate protein. Rat groups for each compound were: (1) experimental-compound-infused and ad libitum-fed, (2) isoenergetic glucose-infused and pairfed, and (3) saline infused and pair-fed. Body-weight changes, N losses and N retention were measured daily. All rats died from partially reduced glucosyl pentaacetoacetate infusion at 100% and 50% of the intended rate. Rats infused with 1-acetoacetamido-2,3-propane diol failed to gain weight and to increase the plasma ketone-body concentration. Glyceryl bisacetoacetate produced hyperketonaemia, and weight gain and N variables that were similar to those for glucose-infused rats. It was concluded that only glyceryl bisacetoacetate would make a satisfactory parenteral nutrient.

Parenteral monoacetoacetin and liver regeneration interaction after partial hepatectomy in the rat.

Parenteral nutrients can be used to manipulate cell proliferation after partial hepatectomy. The relationship among macronutrients--glucose, monoacetoacetin, amino acids--and liver regeneration after partial hepatectomy was investigated. Male rats were anesthetized, received a 70% hepatectomy, and received a low-dose infusion of (1) glucose or (2) monoacetoacetin and a high-dose infusion of (3) glucose, (4) glycerol-glucose, or (5) monoacetoacetin-glucose beginning 6 hours after surgery. The five nonprotein nutrient combinations were infused with and without amino acids. Rats were killed 48 hours after partial hepatectomy, and the label and mitotic indices were determined. Each of the five treatments had a higher label index with amino acids present than with amino acids absent. Low-dose glucose and monoacetoacetin as well as high-dose glucose and glucose-glycerol had higher mitotic indices with amino acids than without amino acids. High-dose monoacetoacetin-glucose was associated with a greater mitotic index than was any other nonprotein substrate treatment, and this response was independent of amino acids being present or absent. In summary, (1) amino acids were needed for maximal cell proliferation rate; (2) the absence of amino acids and not the presence of glucose resulted in reduction of the label and mitotic indices for regenerating liver; (3) high-dose monoacetoacetin increased mitosis with or without amino acids; and (4) monoacetoacetin activity was dose dependent. The results indicate that the best nutrient for treatment of patients with liver injury is acetoacetate. The second best nutrient would be the combination of high-dose glucose and amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)

A 28-day feeding study with ethyl acetoacetate in rats.

Ethyl acetoacetate encapsulated in gum arabic was administered in rodent diet for a minimum of 28 consecutive days to groups of 16 male and 16 female rats (Sprague-Dawley strain) at levels of approximately 100, 300 and 1000 mg/kg body weight/day. A further group of 16 male and 16 female rats was given rodent diet containing gum arabic as a control. The administration of ethyl acetoacetate in the diet did not adversely affect the growth or general health of the animals or their food intakes. None of the minor variations observed in the haematology, serum chemical analyses or urine analyses are considered to be indicative of a treatment-related toxic effect. Caecal enlargement was seen in male rats treated with the top dose of ethyl acetoacetate, but this was accompanied by a normal histopathology. Few histopathological abnormalities were observed. Proteinaceous casts were found in the bladder of approximately half the male rats given 1000 mg ethyl acetoacetate/kg, and nephrocalcinosis was a common occurrence in female rats in this dose group. Renal function was unimpaired in treated male and female rats, and the histopathological findings are common in the strain of rats chosen for this study. Although the caecal enlargement and the changes in kidney and bladder of rats given 1000 mg ethyl acetoacetate/kg are noted, it is considered that ethyl acetoacetate did not produce treatment-related adverse effects in rats during this study.

Interaction of ketosis and liver regeneration in the rat.

Monoacetoacetin, the monoglyceride of acetoacetate, was investigated as a nutritional support for the regenerating liver. Following partial hepatectomy, rats were either fed an oral diet ad libitum or administered by total parenteral feeding glucose alone, monoacetoacetin-glucose mixture, or lipid emulsion-glucose for the nonprotein calories. Five rats from each treatment were killed at 6-hr intervals beginning 12 hr after partial hepatectomy and ending at 72 hr. The number of cells synthesizing DNA and the number of cells in mitosis were compared. Rats fed orally or infused with glucose alone or with lipid emulsion had similar parameters throughout. Rats infused with monoacetoacetin had approximately double the number of cells in mitosis and DNA synthesis compared to the other treatments. This stimulation by monoacetoacetin persisted 72 hr. It was concluded from the data that acetoacetate was the agent responsible for increased DNA synthesis and mitosis, but the mechanism for the stimulation was not identified.

Comparison of monoglyceryl acetoacetate and glucose as parental energy substrate after experimental trauma.

The effects of ketone bodies and glucose on nitrogen balance and liver protein synthesis were studied in rat after experimental trauma. Energy was delivered intravenously as either monoglyceryl acetoacetate (MA; 87.5% of total energy input) or glucose (G). The isocaloric infusions (132 kcal/kg/day) were started after recovery from anaesthesia and continued for 2 days. The liver protein synthesis was then measured in vitro by perfusion with 14C-leucine. The infusion of MA resulted in a more negative cumulative nitrogen balance (MA: -2.31 +/- 0.26 g N/kg, G: -1.32 +/- 0.43 g N/kg/48 h; mean +/- SD) and liver protein synthesis (MA: 43.4 +/- 17.2, G: 71.1 +/- 15.2; arbitrary units, mean +/- SD). The results indicate no benefits from MA during the immediate post-traumatic period.

Parenteral feeding at two hypocaloric levels for comparison of glucose-glycerol mixture with the monoglyceride of acetoacetate on urinary nitrogen losses of the rat.

The monoglyceride of acetoacetate (monoacetoacetin) is a synthetic compound that might serve to reduce the glucose contribution to nonprotein energy in total parenteral nutrition provided it is an effective nutritional source. This study compared monoacetoacetin and glucose-glycerol mixtures as energy in hypocaloric, parenteral feeding of the rat. Four groups of rats were infused with approximately 425 mg N/day along with 11 or 21 kcal/day supplied either by monoacetoacetin or the glucose-glycerol mixture. Body weight and urinary nitrogen were followed for 7 days, and leucine kinetics was measured on day 7. At 11 or 21 kcal/day, rats infused with the monoacetoacetin or the glucose-glycerol mixture had similar body weight losses, urinary nitrogen losses, leucine flux and leucine oxidation rates. When rats receiving the same energy substrate at 11 or 21 kcal/day were compared, the rats receiving the 21 kcal/day by vein lost less body weight and less urinary nitrogen and had a smaller leucine flux. The leucine oxidation rate was unchanged. These data demonstrate that alterations in nitrogen parameters are dependent on the quantity of energy but are independent of the source of energy when monoacetoacetin and glucose-glycerol mixtures are compared. Monoacetoacetin interacts with nitrogen metabolism in healthy rats as effectively a glucose-glycerol mixtures at the hypocaloric levels studied.