Ketone bodies are small lipid-derived molecules that provide circulatory energy to tissues during times of hunger or prolonged exercise. More than 80% of the stored energy in the human body is found as fatty acids in adipose tissue. Muscle and liver glycogen stores are depleted first during starvation.[1] Then, the fatty acids are recruited from the adipocytes and transferred to the liver to be converted into ketone bodies. The ketone bodies are subsequently distributed through the circulation to metabolically active tissues like muscle and the brain, where they are metabolized to acetyl coenzyme A (acetyl-CoA) and utilized as a glucose-sparing energy source.[2]Acetoacetate, acetone, and beta-hydroxybutyrate (β-hydroxybutyrate) are the components of ketone bodies.[3] Acetoacetate is a precursor to acetone and β-hydroxybutyrate. The most frequent ketone body in circulation is β-hydroxybutyrate.[2]
Ketone bodies are involved in several metabolic processes, including fatty acid β-oxidation, the tricarboxylic acid cycle (TCA), gluconeogenesis, de novo lipogenesis (DNL), and sterol biosynthesis. In humans, ketone body metabolism is utilized to nourish the brain during times of nutritional deficiency.
Ketones contribute significantly to overall energy metabolism by acting as energy fuels for extrahepatic tissues such as the brain, heart, or skeletal muscle in a variety of physiological conditions such as body oxidation, hunger, the neonatal period, post-exercise, pregnancy, and low-carbohydrate diets. Total circulatory ketone body concentrations in healthy adult humans typically oscillate between 100 and 250 µM, increase to 1 mm≥ after prolonged exercise or 24 hours of fasting, and can accumulate up to 20 mm in conditions such as ketosis, ketonuria, diabetic ketoacidosis.[4,5]
Ketone bodies have essential functions in mammalian cell metabolism, homeostasis, and signaling under a range of physiological and pathological situations, according to researchers. They are also key signaling agents, drivers of protein post-translational modification (PTM), and modulators of inflammation and oxidative stress.[4,6]
KETOGENESIS
Ketogenesis is a chain of reactions that results in the formation of ketone bodies.[7] When glycogen supplies are severely depleted or the concentration of fatty acids rises, the production of ketone bodies increases. When glucose is not readily accessible, the brain turns to ketone bodies as its primary source of energy. The reason behind this is, in contrast to other bodily organs, the brain has a strict minimum demand for glucose.The decrease in hepatic glycogen concentration and the glucagon-insulin ratio are among the factors that stimulate ketogenesis. Low insulin results in an increase in free fatty acids that are transported to the mitochondria, enhancing the formation of ketone bodies.[8]
Ketogenesis requires mitochondrial β-oxidation of fatty acids.[9] Carnitine palmitoyltransferase (CPT-1) introduces fatty acids into the mitochondria, where they are broken down into acetyl-CoA by β-oxidation. The enzyme thiolase converts two acetyl-CoA molecules to acetoacetyl coenzyme A (acetoacetyl-CoA). Following that, acetoacetyl-CoA is transformed into hydroxymethylglutaryl-coenzyme A (HMG-CoA). HMG-CoA is also converted to acetoacetate. Non-enzymatic decarboxylation converts acetoacetate to acetone or β-hydroxybutyrate and ketone bodies are formed. When ketone bodies increase, free fatty acids decrease, and ketogenesis is suppressed so that ketone bodies do not accumulate dangerously in the blood, resulting in ketoacidosis.[8] Ketolysis, on the contrary, is the inverse process of ketogenesis. It is a series of processes that take place to replenish the energy of ketone bodies. It occurs in nearly every cell.[10]
Hyperketonemia
Irregularities in the level of carbohydrates in plasma induce variable degrees of hyperketonemia.[11] While the post-meal plasma concentration [KC] is <0.1 mM, ketone body concentrations more than 0.2 mM are considered hyperketonemia.[3]
EFFECTS OF KETONE BODIES ON BRAIN
The human brain is a structure with highly developed skills such as comprehending, feeling, and reasoning, as well as a high energy need. Although the brain accounts for only 2% of body weight, the energy it uses at rest accounts for 20% of overall energy consumption.[12,13] Neurons consume 70-80% of the brain’s energy, while glial cells consume the rest.[14]
The concentration of ketones in the blood influences their usage in the brain.[15] When glucose becomes scarce, ketones provide an alternate source of energy for the brain.[16] The utilization of ketone bodies in the adult brain is considerably reduced during satiety.[17] However, adults utilize ketone bodies during extended hunger, such as fasting.[18,19] During the development stage, ketones are regarded as one of the basic energy sources of the brain, meeting 70% of the energy needed.[20]
Metabolic and Signaling Roles of Ketone Bodies
Ketones appear to be dependent on ketosis for the appropriate development and operation of a healthy neonatal brain since they are a source of energy and precursors for fatty acids and cholesterol, which make up the majority of the brain’s dry matter.[3,21,22] Therefore, continual ketone production is normal in newborns to some extent. Blood β-hydroxybutyrate (BHB) levels in healthy newborns rise to roughly 0.5-2 mM within 12 hours of birth and remain elevated for at least a week.[23] Many human infant tissues, particularly the brain, have significant amounts of ketone absorption and oxidation. In the perfused premature baby brain, for example, the molar consumption of BHB is approximately 50% more than that of glucose.[24] Preclinical research in other model species, particularly nursing mice, supports the relevance of ketone bodies in brain development.[3,20,25] The damage to brain cells caused by hypoxia is known as hypoxic-ischemic encephalopathy (HIE). Since the newborn brain is designed to accept and utilize ketone bodies, maintaining enough ketosis in post-HIE newborns has the potential to ameliorate many of the brain’s degenerative processes. In addition, because the endogenous ketogenesis mechanism takes many hours to occur, endogenous ketosis cannot achieve high blood ketone levels during the 6-hour latent period of HIE brain damage. This suggests that exogenous ketones can be administered to preserve cellular function during the latent and secondary phases of damage. Exogenous ketones may potentially contribute to long-term healing processes due to their possible neurotrophic effects and role as synthetic precursors.[26,27] Exogenous ketones, including ketogenic medium-chain fatty acids (MCFAs), ketone mineral salts, BHB, or the ketone bodies acetoacetate (AcAc), are typically found as ketone bodies, liquids containing ketone precursors, or soluble powders. Ketone bodies, which can be derived from both endogenous and exogenous sources, are processed uniformly within the body. While there are certain limits to using exogenous ketones, the majority of these constraints are less likely to cause issues in babies getting active therapy for HIE in an intensive care setting.[26] While the evidence supporting the neuroprotective benefits of ketone bodies for newborn brain damage is still in its early stages, an important working group has reported neuroprotection resulting from the injection of exogenous ketone bodies in a range of adult brain injury animal models. The study in question contains numerous Alzheimer’s disease (AD) models, as well as stroke, Parkinson’s disease (PD), and traumatic brain injury (TBI).[6,26] Alzheimer’s disease is a neurological disorder that causes memory loss and cognitive impairment.[28-30] The main features of AD pathology include the accumulation of amyloid-beta (Aβ) plaques followed by the formation of neurofibrillary tangles (NFTs).[31,32] Microglia enhance Aβ and tau clearance in response to Aβ aggregation, providing physical barriers to shield neurons from neurotoxic plaque but also causing neuroinflammation, which damages neurons.[28]
The ketogenic diet is a high-fat, low-carbohydrate diet regimen that stimulates the breakdown of fatty acids and ketogenic amino acids; this diet is a process that results in the production of ketone bodies that can be further metabolized for energy production. Blood β-hydroxybutyrate, one of the three ketone bodies, has been found at considerably reduced levels in the blood of AD patients.[28,33]
According to a study, a ketogenic diet can promote changes in synaptic morphology and function involving ionic channels or synaptic vesicular loop mechanisms, hence increasing motor performance. As a result, the ketogenic diet is linked to disorders defined by these processes. Several motor dysfunction disorders, such as epilepsy, metabolic disorders, cancers, autism, depression, migraine, narcolepsy, PD, and AD, can sample these diseases. Motor dysfunction can also be called motor learning disabilities. It is a developmental coordination disorder.[34]
With BHB therapy, reduced cortical plaque development was found in the mouse model of AD, resulting in lower cortical plaque volume and less prominent microgliosis. In this circumstance, increasing the amount of BHB is a potential approach for AD.[28] BHB therapy resulted in decreased plaque development in mice, according to the studies. Blood β-hydroxybutyrate must be able to pass the blood-brain barrier to be used as a treatment agent for AD. Endothelial cells in blood vessels in the brain convey monocarboxylate carriers, which mediate ketone body transport via crossing the blood-brain barrier.[35,36] Many clinical trials are presently ongoing as a result of the recent surge in interest in the use of ketosis as a treatment or adjuvant in a variety of neurological disorders. These include studying the metabolism of exogenous ketones in healthy human adults, as well as the feasibility and efficacy of ketosis in treating AD and PD, as well as adult stroke and cardiac arrest.[26]
The β-oxidation of fatty acids during ketogenesis might be harmful.[37] While increased oxygen consumption for fatty acid oxidation leads to dysfunctional adenosine triphosphate (ATP) synthesis, it also raises the likelihood that the environment of neurons in the brain parenchyma will become hypoxic, where the oxygen pressure is not uniform and is relatively low.[8] Simultaneously, the utilization of ketone bodies in neurons, as well as their inclination toward glycolysis, might result in a drop in nicotinamide adenine dinucleotide phosphate (NADPH), increased oxidative stress, and cell death.[38] Depending on the circumstances, pregnant women with diabetes should avoid ketoacidosis because of the risk of low intelligence quotient (IQ) in their children.[39]
Although ketone bodies are used as an energy source, their accumulation has several negative consequences, including diabetic ketoacidosis, brain damage, and hypoxia. Ketoacidosis is the presence of high doses of ketone bodies in the blood. Ketoacidosis is associated with a high mortality and morbidity rate.[40] Patients with ketoacidosis had infectious conditions such as vomiting, malnutrition, and gastroenteritis. Decompensation is described as a decline in the heart’s working power; the frequency and length of episodes influence morbidity. Morbidity and mortality can be avoided with efficient treatment and measures implemented in the presence of the catabolic process as a result of the patient’s diagnosis.[41]
KETOSIS
Ketosis is defined as a rise in ketone levels in the blood for a variety of causes. This rise might be due to either physiological ketosis or pathological ketosis.[16,42]
Physiological Ketosis
The level of ketone bodies in the blood increases during physiological ketosis, although this increase does not reach harmful levels.
a. Hunger: In the case of fasting or hunger, ketogenesis is initiated to maintain energy balance and continuity throughout the body, particularly to supply fuel to the brain.[43]
b. The ketogenic diet: Fat-rich diets induce a rise in the number of ketone bodies in the blood. The ketogenic diet has not become widely used, since it raises the risk of systemic problems such as growth retardation, nephrolithiasis, and hyperlipidemia.[44]
c. Age and energy demand: Newborn babies’ ketone bodies are increased by high-fat milk.[45] In children, the amount of blood ketone bodies and age are inversely associated. The amount of blood ketone bodies declines with aging.[46] High blood ketone body concentrations are also common in pregnant women. They become more susceptible to ketoacidosis as a result.[47]
Pathological Ketosis
Pathologic ketosis is a state of dangerously elevated ketone bodies in the blood brought on by anomalies in ketone metabolism, which alters the pH of the blood.[16,42]
a. Impaired ketolysis pathway: People with a deficit in a ketolysis-related enzyme and those with congenital anomalies in ketogenesis have issues with blood ketone body levels.[16]
b. Alcoholic ketoacidosis: Alcoholic ketoacidosis is a condition caused by excessive ethanol consumption. Excessive alcohol intake promotes ethanol oxidation, which raises the number of ketones in the blood, resulting in ketoacidosis.[48]
c. Diabetic ketoacidosis: Ketogenesis is reported to be enhanced in diabetic individuals due to insulin deficiency. It is the most significant factor responsible for the increase in pathological ketosis.[49] Oxidative damage has been found in the brains of diabetic ketoacidosis patients.[50,51] Cerebral edema, hemorrhagic stroke, intracerebral complications, and neurological impairment are all possible causes of diabetic ketoacidosis.[52-54]
In conclusion, acetyl-CoA, the usual result of fatty acid oxidation in the liver, is converted into ketones, which are acidic molecules. When blood glucose levels fall, endogenously generated ketone bodies in the liver are transferred to the brain and utilized as fuel. They offer a considerable portion of the required energy in situations such as extended fasting and hunger. Ketone bodies can also be administered exogenously. In case of excessive administration or a genetic defect in ketogenesis enzymes, ketone bodies accumulate in people’s blood and cause ketoacidosis. Fasting or hunger causes a rise in blood ketone levels, however, this is not on a harmful level and does not result in ketoacidosis. On the other hand, ketone bodies are one of the brain’s primary energy sources during development. Ketone bodies have shown neuroprotective effects, leading to potential advancements in diseases characterized by motor dysfunction, such as AD and PD. That is why individuals suffering from neurological diseases are encouraged to follow a ketogenic diet. According to the findings of this review, ketone bodies are advantageous to the brain; however, too much accumulation in the blood is hazardous.