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The interconversion and disposal of ketone bodies in untreated and injured post-absorptive rats.

ABSTRACT: [3-(14)C]Acetoacetate and beta-hydroxy[3-(14)C]butyrate were used to investigate the kinetics of ketone body metabolism in rats 3h after bilateral hind-limb ischaemia and in controls, both groups being in the post-absorptive state and in a 20 degrees C environment. Calculations were carried out as described by Heath & Barton (1973) and the following conclusions were reached. 1. In both injured and control rats, the rates of irreversible disposal (extrahepatic utilization) of beta-hydroxybutyrate and acetoacetate were proportional within experimental error to their blood concentrations up to at least 0.4mm (the maximum found in these rats), implying that they were determined, via these concentrations, by the rates of production by the liver. 2. Conversion of blood beta-hydroxybutyrate into blood acetoacetate took place mainly in the liver, but the reverse process occurred mainly in extrahepatic tissues. 3. The ;metabolic clearance rate' (the volume of blood which, if completely cleared of substrate in unit time, would give a disposal rate equal to that in the whole animal) was calculated for beta-hydroxybutyrate and acetoacetate. Comparison with the cardiac output showed that in control rats the proportion of circulating beta-hydroxybutyrate extracted was lower than that of acetoacetate, clearance of which appeared almost complete. After injury both metabolic clearance rates decreased, probably because of the lower cardiac output. 4. After injury, because the average blood concentrations of ketone bodies, especially acetoacetate, were higher, the mean total rate of disposal also increased. Assuming complete oxidation, the mean contribution of ketone bodies to the whole body O(2) consumption rose from 7 to 15%.

SUBMITTER: Barton RN

PROVIDER: S-EPMC1165987 | biostudies-other | 1973 Nov

REPOSITORIES: biostudies-other

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Project description:BackgroundCancer Anorexia Cachexia Syndrome (CACS) is a distinct atrophy disease negatively influencing multiple aspects of clinical care and patient quality of life. Although it directly causes 20% of all cancer-related deaths, there are currently no model systems that encompass the entire multifaceted syndrome, nor are there any effective therapeutic treatments.MethodsA novel model of systemic metastasis was evaluated for the comprehensive CACS (metastasis, skeletal muscle and adipose tissue wasting, inflammation, anorexia, anemia, elevated protein breakdown, hypoalbuminemia, and metabolic derangement) in both males and females. Ex vivo skeletal muscle analysis was utilized to determine ubiquitin proteasome degradation pathway activation. A novel ketone diester (R/S 1,3-Butanediol Acetoacetate Diester) was assessed in multifaceted catabolic environments to determine anti-atrophy efficacy.ResultsHere, we show that the VM-M3 mouse model of systemic metastasis demonstrates a novel, immunocompetent, logistically feasible, repeatable phenotype with progressive tumor growth, spontaneous metastatic spread, and the full multifaceted CACS with sex dimorphisms across tissue wasting. We also demonstrate that the ubiquitin proteasome degradation pathway was significantly upregulated in association with reduced insulin-like growth factor-1/insulin and increased FOXO3a activation, but not tumor necrosis factor-α-induced nuclear factor-kappa B activation, driving skeletal muscle atrophy. Additionally, we show that R/S 1,3-Butanediol Acetoacetate Diester administration shifted systemic metabolism, attenuated tumor burden indices, reduced atrophy/catabolism and mitigated comorbid symptoms in both CACS and cancer-independent atrophy environments.ConclusionsOur findings suggest the ketone diester attenuates multifactorial CACS skeletal muscle atrophy and inflammation-induced catabolism, demonstrating anti-catabolic effects of ketone bodies in multifactorial atrophy.

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The interconversion and disposal of ketone bodies in untreated and injured post-absorptive rats.

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