The Brain Hypometabolism Hypothesis Part 66: Physiological Factors Influencing BrAce


From the Top Down – Acetone, Acetoacetic Acid, Beta-Hydroxybutyric Acid by Edgar181 (Public Domain)

There are a number of factors that influence Breath Acetone levels. Breath Acetone levels can be markedly increased in conditions such as ketoacidosis. However the focus here is on physiological states. The paper referenced below identifies several factors that influence BrAce based on the research literature. Exercise is associated with an increase in BrAce. Caloric intake is inversely related to BrAce.

Context of Breath Acetone Levels

There is a paper on Acetone measurement in the breath published recently. Breath Acetone levels give a useful insight into Ketone metabolism.

What is Acetone?

Acetone has the chemical formula (CH3)2CO and is a Ketone body. Acetone is produced by the Decarboxylation of Acetoacetate. Acetone has a number of uses. Acetone can be converted to Lactic acid in the liver and then into Pyruvic acid which can be converted into Acetyl CoA.

What is Acetoacetate?

Acetoacetate is a Ketone Body with the chemical formula C4H5O3-. Acetoacetate is the conjugate base of Acetoacetic Acid (which is shown in the diagram above). Acetoacetic Acid is a weak acid.

Acetoacetic acid can be produced by the hydrolysis of Diketene which in turn is derived from the dehydration of Acetic Acid which is a key ingredient in vinegar.

In the body, Acetoacetate is derived from Acetyl CoA in the mitochondria in the liver.

The concept of conjugate acid/base pairs derives from the Brønsted–Lowry theory which states that a base receives a proton to become a conjugate acid and that an acid donates a proton to become a conjugate base.

What is Beta-Hydroxybutyrate?

Beta-Hydroxybutyrate is a Ketone Body with the chemical formula C4H8O3.

Beta-Butoxybutyrate is the conjugate base of Beta-Butoxybutyric Acid (which is shown in the diagram above). Beta-Butoxybutyric Acid is a weak acid and is found in two forms as enantiomers (an L and D form). D-3-hydroxybutyrate is derived from Acetoacetate in the liver.

The concept of conjugate acid/base pairs derives from the Brønsted–Lowry theory which states that a base receives a proton to become a conjugate acid and that an acid donates a proton to become a conjugate base.

What is Decarboxylation?

Decarboxylation is the removal of a Carboxyl group (COOH).

What are Ketone Bodies?

Ketone bodies are products of fatty acid metabolism (White and Venkatash, 2011). The three main Ketone bodies are

  • Acetoacetate
  • Beta-Hydroxybutarate
  • Acetone

What is a Ketone?


Ketone Structure (Public Domain) by Benjah-bmm27

A Ketone is a chemical compound in which a Carbonyl group (a Carbon atom with a double bond (4 electrons) to an Oxygen atom) binds to 2 Carbon atoms (IUPAC, 2017).

Brain Hypometabolism Hypothesis

The Brain Hypometabolism Hypothesis focuses on energy metabolism. More specifically the hypothesis states that

Energy hypometabolism in the brain leads to neuropathology


Human Metabolism by Frozen Man (CC BY 4.0)

What is Metabolism?

Metabolism can be defined as the chemical processes that occur in living organisms. There are three types of metabolic processes

(a) Generation of energy

(b) Generation of basic chemicals including fatty acids, amino acids and sugars

(c) Elimination of Nitrogen waste products



Glycolysis by Dr Thomas Shafee (CC BY 4.0)

Glycolysis is one of the key pathways for energy metabolism in the human body. In this metabolic pathway the molecule Glucose is converted into Pyruvate. This pathway generates energy in the form of ATP. This pathway however does not use oxygen although the products generated are metabolised using oxygen. This is relevant to the bigger picture of energy metabolism in the brain.


Acetyl CoA Space Filling Molecule by Benjah-bmm27 (Public Domain)

Acetyl Coenzyme A is an important molecule for many pathways involved in energy metabolism. Acetyl Coenzyme A is derived from

(a) Glucose via the Glycolysis pathway

(b) Amino acids via Acetoacetyl-CoA, Pyruvate and directly through multiple pathways

(c) Fatty acids via Beta-oxidation

Vitamin B5 is required for the synthesis of Acetyl CoA.

The Citric Acid Cycle

The Citric Acid Cycle (CC BY 3.0) by Narayanese, WikiUserPedia, YassineMrabet, TotoBaggins, Wadester16

The Citric Acid Cycle is one of the main energy metabolism pathways in humans. Acetyl Co-A which is generated from other pathways is utilised in the Citric Acid Cycle. The Citric Acid Cycle has a number of properties

  1. Generation of energy in the form of ATP
  2. Generating NADH which is utilised in oxidative phosphorylation
  3. Citric Acid is regenerated
  4. Carbon Dioxide is produced

The Citric Acid Cycle takes place in the Mitochondria.

The Citric Acid Cycle is important for the discussion of the Brain Hypometabolism Hypothesis where we have already discussed the metabolism of Glucose.


IUPAC. Compendium of Chemical Terminology, 2nd ed. (the “Gold Book”). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). XML on-line corrected version: (2006-) created by M. Nic, J. Jirat, B. Kosata; updates compiled by A. Jenkins. ISBN 0-9678550-9-8. Last update: 2014-02-24; version: 2.3.3. DOI of this term: Accessed 8th May 2017.

White H1, Venkatesh B. Clinical review: ketones and brain injury. Crit Care. 2011 Apr 6;15(2):219. doi: 10.1186/cc10020.

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