Exogenous ketones are a class of

ketone bodies Ketone bodies are water-soluble molecules that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acetyl- ...

that are ingested using

nutritional supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...

s or foods. This class of ketone bodies refers to the three water-soluble

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

s (

acetoacetate Acetoacetic acid (also acetoacetate and diacetic acid) is the organic compound with the formula CHCOCHCOOH. It is the simplest beta-keto acid, and like other members of this class, it is unstable. The methyl and ethyl esters, which are quite stab ...

, β-hydroxybutyrate �-HB and

acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscib ...

). These ketone bodies are produced by interactions between macronutrient availability such as low

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

and high free fatty acids or

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

signaling such as low

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

and high

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...

cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...

. Under physiological conditions, ketone concentrations can increase due to starvation,

ketogenic diet The ketogenic diet is a high- fat, adequate-protein, low-carbohydrate dietary therapy that in conventional medicine is used mainly to treat hard-to-control (refractory) epilepsy in children. The diet forces the body to burn fats rather than ca ...

s, or prolonged exercise, leading to

ketosis Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability, such as low-carbohydrate diets or fasting, that provides an additional ...

. However, with the introduction of exogenous ketone supplements, it is possible to provide a user with an instant supply of ketones even if the body is not within a state of ketosis before ingestion. However, drinking exogenous ketones will not trigger fat burning like a ketogenic diet. Most supplements rely on β-hydroxybutyrate as the source of exogenous ketone bodies. It is the most common exogenous ketone body because of its efficient energy conversion and ease of synthesis. In the body, β-HB can be converted to acetoacetic acid. It is this acetoacetic acid that will enter the energy pathway using beta-ketothialase, becoming two

Acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...

molecules. The Acetyl CoA is then able to enter the

Krebs cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...

in order to generate ATP. The remaining β-HB molecules that aren't synthesized into acetoacetic acid are then converted to acetone through the acetoacetate decarboxylase waste mechanism.

Structure

Acetoacetate is produced in the

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

of liver cells by the addition of an acetyl group from acetyl CoA. This creates 3-hydroxy-3-methylgluteryl CoA which loses an acetyl group, becoming acetoacetate. Beta-Hydroxybutyric_acid-2D-skeletal

β-Hydroxybutyrate is also synthesized within liver cells; this is accomplished through the metabolism of fatty acids. Through a series of reactions, acetoacetate is first produced; and it is this acetoacetate that is reduced into β-hydroxybutyrate, catalyzed by the β-hydroxybutyrate dehydrogenase enzyme. Although, β-hydroxybutyrate is technically not a ketone due to the structure of the molecule (OH- attached to carbonyl group makes this an acid), β-HB acts like a ketone, providing the body with energy in the absence of glucose. In fact, β-Hydroxybutyrate is the most abundant ketone-like molecule in the blood during ketosis. Acetone-2D-skeletal

Acetone is an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...

with the formula (CH3)2CO and is one of the simplest and smallest ketones. It is synthesized from the breakdown of acetoacetate in ketotic individuals within the liver.

Types

Ketone salts

Ketone salts are usually a synthetic compound of Beta-hydroxybutyric acid, also known as βHB. It is then bonded to sodium, potassium, magnesium, and/or calcium to offset the acidic nature of βHB alone. Most ketone salts are racemic which means only half of it is bioavailable, resulting in double the salt load per D-bhb, and even less bioavailability.

Ketone esters

There are multiple molecules that qualify as a "Ketone Ester." The most researched ketone ester, or ketone monoester, is called D-Beta Hydroxybutyrate/ D 1,3-butanediol monoester, which is a naturally derived compound through a fermentation process. It was created by Dr. Richard Veech and Todd King at the NIH, and then commercialized by companies including KetoneAid and TDeltaS, and previously by HVMN, a Silicon Valley-based technology company. This monoester links the same beta-hydroxybutyric acid found in ketone salts but bonded with D 1,3-butanediol (also called R 1,3 butanediol) instead of bases (salts). The first part of the metabolism of this monoester takes place in the digestive system (fast release), followed by the remaining portion taking place in the liver (slow release). The metabolic structure of D-Beta Hydroxybutyrate/ D 1,3-butanediol monoester is similar to that of MCT C8 oil, but many times stronger and without GI issues.

Other ketone esters

Technically there are other ketone esters such as acetoacetate/ D/L 1,3-butanediol (racemic). This diester has been tested more with deep sea divers. It is not commercially available. Another ketone ester is also referred to as a ketone di-ester which is a bond of C6 and R 1,3 butanediol. It is recommended to be consumed with food and is commercialized by Juvenescence Labs.

Effects

The consumption of ketone bodies results in several effects, ranging from reduced glucose utilization in peripheral tissues, anti-lipolytic effects on adipose tissue, and reduced

proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...

in skeletal muscle. In addition to this, ketone bodies serve as signaling molecules that regulate gene expression and adaptive responses. When exogenous ketone bodies are ingested, acute and nutritional exogenous ketosis is produced.

Blood

In human blood, ketone ester and ketone salt consumption deliver a >50% higher plasma concentration of D-β-Hydroxybutyrate, an

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

of regular β-HB. In terms of efficacy, the blood D-βHB concentrations are higher when using ketone esters instead of ketone salts (KE = 2.8±0.2 mM; KS = 1.0±mM). This is due to the fact that the KE supplement contains >99% of the D-βHB-isoform while the KS supplement contains ~50% of the L-βHB-isoform, which is metabolized much slower than the D-βHB-isoform. Also, ketone salt supplements slightly raise the blood pH level. This is mainly due to the

conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...

action of βHB (βHB-) which fully dissociates within the blood; this mildly raises the blood and urine pH which is further increased as the kidneys to excrete the excess

cations An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

(Na+, Ca+, K+). Ketone esters reduce the blood pH because KE

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

proves β-HB with butanediol. These two undergo hepatic metabolism, forming a keto-acid.

Hormones

Exogenous ketones lower blood glucose concentrations. Although

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ma ...

stores are plentiful, ketones lower the blood glucose because they limit hepatic gluconeogenesis and increase peripheral glucose intake. They have also been known to reduce hunger and the desire to eat. This is shown by the decreased levels of the hunger hormone,

ghrelin Ghrelin (; or lenomorelin, INN) is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highe ...

. In addition, it has been surmised that exogenous ketones may stimulate

secretion. Following exposure to exogenous ketones, small amounts of secreted insulin have been reported in animals. However, because insulin has also been shown to increase in subjects who took an exogenous ketone supplement and dextrose drink, in addition to those who only took the exogenous supplement, more research remains to be seen on the effects of ketone supplements on insulin.

References

{{reflist Dietary supplements