Ketone-body metabolism in tumour-bearing rats.
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ABSTRACT:
SUBMITTER: Rofe AM
PROVIDER: S-EPMC1153051 | biostudies-other | 1986 Jan
REPOSITORIES: biostudies-other
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Project description:1. In short- and long-term diabetic rats there is a marked increase in size of both the small intestine and colon, which was accompanied by marked decreases (P less than 0.001) and increases (P less than 0.001) in the arterial concentrations of glutamine and ketone bodies respectively. 2. Portal-drained viscera blood flow increased by approx. 14-37% when expressed as ml/100 g body wt., but was approximately unchanged when expressed as ml/g of small intestine of diabetic rats. 3. Arteriovenous-difference measurements for ketone bodies across the gut were markedly increased in diabetic rats, and the gut extracted ketone bodies at approx. 7 and 60 nmol/min per g of small intestine in control and 42-day-diabetic rats respectively. 4. Glutamine was extracted by the gut of control rats at a rate of 49 nmol/min per g of small intestine, which was diminished by 45, 76 and 86% in 7-, 21- and 42-day-diabetic rats respectively. 5. Colonocytes isolated from 7- or 42-day-diabetic rats showed increased and decreased rates of ketone-body and glutamine metabolism respectively, whereas enterocytes of the same animals showed no apparent differences in the rates of acetoacetate utilization as compared with control animals. 6. Prolonged diabetes had no effects on the maximal activities of either glutaminase or ketone-body-utilizing enzymes of colonic tissue preparations. 7. It is concluded that, although the epithelial cells of the small intestine and the colon during streptozotocin-induced diabetes exhibit decreased rates of metabolism of glutamine, such decreases were partially compensated for by enhanced ketone-body utilization by the gut mucosa of diabetic rats.
| S-EPMC1148739 | biostudies-other
Project description:1. The effects of starvation and diabetes on brain fuel metabolism were examined by measuring arteriovenous differences for glucose, lactate, acetoacetate and 3-hydroxybutyrate across the brains of anaesthetized fed, starved and diabetic rats. 2. In fed animals glucose represented the sole oxidative fuel of the brain. 3. After 48h of starvation, ketone-body concentrations were about 2mm and ketone-body uptake accounted for 25% of the calculated O(2) consumption: the arteriovenous difference for glucose was not diminished, but lactate release was increased, suggesting inhibition of pyruvate oxidation. 4. In severe diabetic ketosis, induced by either streptozotocin or phlorrhizin (total blood ketone bodies >7mm), the uptake of ketone bodies was further increased and accounted for 45% of the brain's oxidative metabolism, and the arteriovenous difference for glucose was decreased by one-third. The arteriovenous difference for lactate was increased significantly in the phlorrhizin-treated rats. 5. Infusion of 3-hydroxybutyrate into starved rats caused marked increases in the arteriovenous differences for lactate and both ketone bodies. 6. To study the mechanisms of these changes, steady-state concentrations of intermediates and co-factors of the glycolytic pathway were determined in freeze-blown brain. 7. Starved rats had increased concentrations of acetyl-CoA. 8. Rats with diabetic ketosis had increased concentrations of fructose 6-phosphate and decreased concentrations of fructose 1,6-diphosphate, indicating an inhibition of phosphofructokinase. 9. The concentrations of acetyl-CoA, glycogen and citrate, a potent inhibitor of phosphofructokinase, were increased in the streptozotocin-treated rats. 10. The data suggest that cerebral glucose uptake is decreased in diabetic ketoacidosis owing to inhibition of phosphofructokinase as a result of the increase in brain citrate. 11. The inhibition of brain pyruvate oxidation in starvation and diabetes can be related to the accelerated rate of ketone-body metabolism; however, we found no correlation between the decrease in glucose uptake in the diabetic state and the arteriovenous difference for ketone bodies. 12. The data also suggest that the rates of acetoacetate and 3-hydroxybutyrate utilization by brain are governed by their concentrations in plasma. 13. The finding of very low concentrations of acetoacetate and 3-hydroxybutyrate in brain compared with plasma suggests that diffusion across the blood-brain barrier may be the rate-limiting step in their metabolism.
| S-EPMC1166169 | biostudies-other
Project description:Ketone bodies, including β-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. β-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system. Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma acetoacetate levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, Gpr43-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, Gpr43-deficient mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods.
| S-EPMC6876247 | biostudies-literature
Project description:Mice bearing the Lewis lung carcinoma showed a high tumour glutaminase activity and significantly higher concentrations of most amino acids than in both the liver and the skeletal muscle of the host. Tumour tissue slices showed a marked preference for glutamine, especially for oxidation of its skeleton to CO2. It is proposed that the metabolism of this particular carcinoma is focused on amino acid degradation, glutamine being its preferred substrate.
| S-EPMC1148723 | biostudies-other
Project description:Background:Metabolic remodeling plays a vital role in the development of heart failure. The trimetazidine can optimize fatty acid and glucose oxidation via inhibition of long-chain 3-ketoacyl CoA thiolase in the heart. So, trimetazidine commonly used in cardiovascular therapy as a myocardial metabolic drug. This study was conducted to assess the effects and mechanisms of trimetazidine on ketone body metabolism in heart failure rats. Methods:A rat model of heart failure was established by continuous subcutaneous injection of isoproterenol in 10 mg/kg/d. We examined body weight, heart weight index, and tested B-type natriuretic peptide by kit. We detected the structure and function of the heart. Hematoxylin-eosin staining and Masson's trichrome staining was performed to assess myocardial tissue morphology. To evaluate apoptosis, we used Tunel staining. Metabolic substrate contents of glucose, free fatty acid, ketone bodies, lactic acid, and pyruvate and ATP levels in myocardial tissues were measured with the corresponding kit. We detected the levels of protein expressions related to myocardial substrate uptake and utilization by Western blot. Results:Trimetazidine remarkably reduced the heart weight index and B-type natriuretic peptide levels. Besides, trimetazidine increased the level of blood pressure and decreased heart rate. Moreover, trimetazidine inhibited decreases in left ventricular ejection fraction and left ventricular fractional shortening. Further, trimetazidine decreased the levels of collagen volume fraction and promoted ATP production in myocardial tissues. Trimetazidine also reduced the levels of free fatty acid, ketone bodies, lactic acid, and increased glucose and pyruvate levels in myocardial tissues. Furthermore, trimetazidine markedly inhibited apoptosis. More importantly, the protein expression levels related to myocardial substrate uptake and utilization increased dramatically in the trimetazidine group. In particular, the protein expressions related to ketone body utilization were prominent. Conclusions:Trimetazidine could attenuate metabolic remodeling and improve cardiac function in heart failure rats. The potential mechanism for the cardioprotective effect of trimetazidine may be highly associated with its regulation of adenosine monophosphate-activated protein kinase, and peroxisome proliferator activated receptor ? expressions. Along with the regulation, myocardial substrate utilization was improved, especially the utilization of ketone bodies.
| S-EPMC7457052 | biostudies-literature
Project description:The aim of this work was to investigate the use of 13 C-labelled acetoacetate and ?-hydroxybutyrate as novel hyperpolarized substrates in the study of cardiac metabolism. [1-13 C]Acetoacetate was synthesized by catalysed hydrolysis, and both it and [1-13 C]?-hydroxybutyrate were hyperpolarized by dissolution dynamic nuclear polarization (DNP). Their metabolism was studied in isolated, perfused rat hearts. Hyperpolarized [1-13 C]acetoacetate metabolism was also studied in the in vivo rat heart in the fed and fasted states. Hyperpolarization of [1-13 C]acetoacetate and [1-13 C]?-hydroxybutyrate provided liquid state polarizations of 8 ± 2% and 3 ± 1%, respectively. The hyperpolarized T1 values for the two substrates were 28 ± 3 s (acetoacetate) and 20 ± 1 s (?-hydroxybutyrate). Multiple downstream metabolites were observed within the perfused heart, including acetylcarnitine, citrate and glutamate. In the in vivo heart, an increase in acetylcarnitine production from acetoacetate was observed in the fed state, as well as a potential reduction in glutamate. In this work, methods for the generation of hyperpolarized [1-13 C]acetoacetate and [1-13 C]?-hydroxybutyrate were investigated, and their metabolism was assessed in both isolated, perfused rat hearts and in the in vivo rat heart. These preliminary investigations show that DNP can be used as an effective in vivo probe of ketone body metabolism in the heart.
| S-EPMC6001529 | biostudies-other
Project description:Rats bearing the Walker-256 carcinosarcoma showed significant changes in leucine metabolism compared with their non-tumour-bearing controls. After a single intravenous tracer dose of L-[1-14C]leucine in vivo, 14CO2 release by tumour-bearing rats was significantly elevated throughout the time course of administration. In addition, both the clearance and turnover rates of the tracer were significantly enhanced in these animals. Incubation of soleus muscles from control and tumour-bearing rats in the presence of L-[1-14C]leucine revealed an enhanced oxidation of the amino acid in the tumour-bearing group. Tumour tissue slices were also able to oxidize the tracer at a similar rate to that found in soleus muscles from control animals.
| S-EPMC1131419 | biostudies-other
Project description:ObjectiveExploitation of protective metabolic pathways within injured myocardium still remains an unclarified therapeutic target in heart disease. Moreover, while the roles of altered fatty acid and glucose metabolism in the failing heart have been explored, the influence of highly dynamic and nutritionally modifiable ketone body metabolism in the regulation of myocardial substrate utilization, mitochondrial bioenergetics, reactive oxygen species (ROS) generation, and hemodynamic response to injury remains undefined.MethodsHere we use mice that lack the enzyme required for terminal oxidation of ketone bodies, succinyl-CoA:3-oxoacid CoA transferase (SCOT) to determine the role of ketone body oxidation in the myocardial injury response. Tracer delivery in ex vivo perfused hearts coupled to NMR spectroscopy, in vivo high-resolution echocardiographic quantification of cardiac hemodynamics in nutritionally and surgically modified mice, and cellular and molecular measurements of energetic and oxidative stress responses are performed.ResultsWhile germline SCOT-knockout (KO) mice die in the early postnatal period, adult mice with cardiomyocyte-specific loss of SCOT (SCOT-Heart-KO) remarkably exhibit no overt metabolic abnormalities, and no differences in left ventricular mass or impairments of systolic function during periods of ketosis, including fasting and adherence to a ketogenic diet. Myocardial fatty acid oxidation is increased when ketones are delivered but cannot be oxidized. To determine the role of ketone body oxidation in the remodeling ventricle, we induced pressure overload injury by performing transverse aortic constriction (TAC) surgery in SCOT-Heart-KO and ?MHC-Cre control mice. While TAC increased left ventricular mass equally in both groups, at four weeks post-TAC, myocardial ROS abundance was increased in myocardium of SCOT-Heart-KO mice, and mitochondria and myofilaments were ultrastructurally disordered. Eight weeks post-TAC, left ventricular volume was markedly increased and ejection fraction was decreased in SCOT-Heart-KO mice, while these parameters remained normal in hearts of control animals.ConclusionsThese studies demonstrate the ability of myocardial ketone metabolism to coordinate the myocardial response to pressure overload, and suggest that the oxidation of ketone bodies may be an important contributor to free radical homeostasis and hemodynamic preservation in the injured heart.
| S-EPMC4209361 | biostudies-literature
Project description:It is becoming evident that type 2 diabetes mellitus is affecting brain energy metabolism. The importance of alternative substrates for the brain in type 2 diabetes mellitus is poorly understood. The aim of this study was to investigate whether ketone bodies are relevant candidates to compensate for cerebral glucose hypometabolism and unravel the functionality of cerebral mitochondria in type 2 diabetes mellitus. Acutely isolated cerebral cortical and hippocampal slices of db/db mice were incubated in media containing [U-13C]glucose, [1,2-13C]acetate or [U-13C]β-hydroxybutyrate and tissue extracts were analysed by mass spectrometry. Oxygen consumption and ATP synthesis of brain mitochondria of db/db mice were assessed by Seahorse XFe96 and luciferin-luciferase assay, respectively. Glucose hypometabolism was observed for both cerebral cortical and hippocampal slices of db/db mice. Significant increased metabolism of [1,2-13C]acetate and [U-13C]β-hydroxybutyrate was observed for hippocampal slices of db/db mice. Furthermore, brain mitochondria of db/db mice exhibited elevated oxygen consumption and ATP synthesis rate. This study provides evidence of several changes in brain energy metabolism in type 2 diabetes mellitus. The increased hippocampal ketone body utilization and improved mitochondrial function in db/db mice, may act as adaptive mechanisms in order to maintain cerebral energetics during hampered glucose metabolism.
| S-EPMC5363491 | biostudies-literature
Project description:Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondrial biogenesis and oxidative phosphorylation capacity in muscle cells. However, leucine-related effects in tumour tissues are still poorly understood. Thus, we described the effects of leucine in both in vivo and in vitro models of a Walker-256 tumour. Tumour-bearing Wistar rats were randomly distributed into a control group (W; normoprotein diet) and leucine group (LW; leucine-rich diet [normoprotein?+?3% leucine]). After 20 days of tumour evolution, the animals underwent 18-fludeoxyglucose positron emission computed tomography (18F-FDG PET-CT) imaging, and after euthanasia, fresh tumour biopsy samples were taken for oxygen consumption rate measurements (Oroboros Oxygraph), electron microscopy analysis and RNA and protein extraction. Our main results from the LW group showed no tumour size change, lower tumour glucose (18F-FDG) uptake, and reduced metastatic sites. Furthermore, leucine stimulated a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, higher mRNA and protein expression of oxidative phosphorylation components, and enhanced mitochondrial density/area even though the leucine-treated tumour had a higher number of apoptotic nuclei with increased oxidative stress. In summary, a leucine-rich diet directed Walker-256 tumour metabolism to a less glycolytic phenotype profile in which these metabolic alterations were associated with a decrease in tumour aggressiveness and reduction in the number of metastatic sites in rats fed a diet supplemented with this branched-chain amino acid.
| S-EPMC6820796 | biostudies-literature