F1000 and the lactate controversy
Question: Hi Tanya,
I am fascinated by development at the Faculty of 1000 started by Y. Ben-Ari. I couldn’t contain myself and posted a comment there. However, I felt a little out of place being just a student arguing with a real scientist. So I still have a couple of questions to ask you.
1. Y Ben-Ari writes there that “Zilberter and Bregestovski and colleagues” dealt with “ketone body metabolites”. What does ketone body metabolite mean? From the articles (Rheims et al., 2009; Holmgren et al., 2010) Y. Ben-Ari refers to, I could only find beta-hydroxybutyrate and basing on my textbook, I thought that ketone bodies are metabolized in the brain resulting in CO2, HCO3- and acetone.”]
2. Y Ben-ari argues with your statement and here’s his exact words: “Zilberter and colleagues have suggested that administration of lactate may be “a novel therapeutic tool to cure Parkinson, Alzheimer, Leigh syndrome and epilepsies”. What did you mean the “tool to cure”?
Answer: Hi Ingrid,
The phrase “ketone body metabolites” is used very scarcely and I’ll give you exact usage of it, then I’ll explain what you probably know already from your textbook.
From those authors who use this phrase, most of them refer to the work of Miles et al. (1), the accurate quote of which is: “ketone body metabolites (CO2, bicarbonate and acetone)” (1). Fontain et al. (2) mention ketone bodies metabolites listing them as beta-hydroxybutyric acid and acetoacetic acid, which is not exactly accurate since they both are ketone bodies themselves.
Other than that, the phrase has a different meaning, like this: “Fatty acids and their ketone body metabolites may serve as afferent signals to modulate food intake” (3). Clearly, ketone bodies are meant as metabolites of fatty acids, again a textbook information.
A citation from very recent reference (4): “Ketone bodies, as described here, comprise acetoacetic acid (AcAc), D-3-hydroxy-n-butyric acid (3HB), and acetone.” Note that they are ketone bodies, not ketone body metabolites.
Now, from the textbook (5): In muscle and brain, ketone bodies yield ATP + CO2 (p. 905); Acetoacetate + H2O -> Acetone + HCO3- (p. 920)
None of the the two articles Y Ben-Ari refers to in his evaluation concerns anything other than beta-hydroxybutyrate, not other ketone bodies, not ATP, CO2 or HCO3-, or acetone.
Your question number 2:
Dr. Ben Ari is twisting the truth by taking the sentence out of context by removing from citation the 6 references we used (in square brackets). What our statement was in reality, was this exact piece from (7):
“… a growing body of evidence shows that metabolic stress caused by impaired energy homeostasis is a common feature of neurodegenerative disorders (NDDs) such as Alzheimer disease, Leigh syndrome, epilepsy, dementia, multiple sclerosis, neuropathies or ataxias  and . We speculate that endogenous ES such as lactate, BHB and pyruvate or their combinations can be efficient in treating NDD, and would address the cause rather than symptoms. Indeed, the neuroprotective effects of pyruvate have been repeatedly demonstrated in cases of brain ischemia, hypoglycemia, hemorragia, stroke and kainate-induced epileptic brain damage , ,  and . Further research into mechanisms of the effects of ES on fundamental neuronal properties might allow more rapid progress in preventing and managing NDDs.”
Updated May 2012. Latest reviews regarding energy metabolism and NDD:
- The ketogenic diet as a treatment paradigm for diverse neurological
- The nervous system and metabolic dysregulation: emerging evidence converges on ketogenic diet therapy
- Carbohydrate-Biased Control of Energy Metabolism: The Darker Side of the Selfish Brain
- Miles J et al., (1980) Determination of 14C radioactivity in ketone bodies: a new, simplified method and its validation. J Lipid Res, 21, 646-650.
- Fontaine M et al. (1996) Acylcarnitine removal in a patient with acyl-CoA beta-oxidation deficiency disorder: effect of L-carnitine therapy and starvation Clinica Chimica Acta 252; 109-122
- Bray GA “A Guide to Obesity and the Metabolic Syndrome: Origins and Treatment” CRC Press, 2011.
- Sass JO (2011). Inborn errors of ketogenesis and ketone body utilization. J Inherit Metab Dis DOI 10.1007/s10545-011-9324-6
- Lehninger, A. L. (2005). in Principles of Biochemistry, 4th Edn, eds D. L. Nelson and M. M. Cox (W. H. Freeman), 690–740.
- Holmgren, C. D., Mukhtarov, M., Malkov, A. E., Popova, I. Y., , P., and Zilberter, Y. 2010). Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity n the neonatal cortex in vitro. J. Neurochem. 112, 900–912.
- Zilberter Y, Zilberter T, Bregestovski P. (2010) Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis. Trends Pharmacol Sci., 31(9):394-401