Ketone Bodies: What Substance Used by the Brain as an Alternative Fuel Source?

January 10, 2026 •

3 min read

Approximately 20% of the body's total energy expenditure at rest is consumed by the brain, despite it only making up about 2% of total body weight. While glucose is the brain's primary fuel, ketone bodies are the substance used by the brain as an alternative fuel source when carbohydrates are scarce. The ability to utilize ketones is a vital metabolic adaptation that allows humans to survive prolonged periods of starvation or low-carbohydrate intake.

Quick Summary

When carbohydrates are limited, the brain can shift its energy source from glucose to ketone bodies. The liver produces these ketones from fatty acids, and they are transported to the brain to serve as an efficient, alternative fuel. This metabolic process, known as ketosis, protects the brain during periods of prolonged fasting or carbohydrate restriction.

Key Points

Ketone Bodies: When carbohydrates are lacking, the liver produces ketone bodies (including BHB and AcAc) from fatty acids as an alternative fuel for the brain.
Ketosis: This metabolic state, where fat is used for fuel instead of glucose, is triggered by very low carbohydrate intake, prolonged fasting, or strenuous exercise.
Crossing the Barrier: Unlike fatty acids, ketone bodies are water-soluble and can effectively cross the blood-brain barrier to fuel brain cells.
Energy Efficiency: Ketones are considered a 'cleaner' and more efficient energy source for the brain than glucose, producing more ATP per carbon with fewer reactive oxygen species.
Neuroprotective Effects: Ketosis is associated with potential neuroprotective benefits, such as reduced inflammation, enhanced antioxidant defenses, and modulated neurotransmitter activity, making it a focus for research on neurological conditions.

Understanding the Brain's Primary Fuel: Glucose

Under normal physiological conditions, the human brain relies almost exclusively on glucose for energy. The brain's high energy demand necessitates a constant and ample supply of fuel. Glucose is readily available from dietary carbohydrates, which are broken down and enter the bloodstream. A constant supply is maintained through liver glycogen stores, but these are depleted relatively quickly during fasting.

The Shift to Alternative Fuel: The Role of Ketone Bodies

When carbohydrate intake is significantly reduced—such as during prolonged fasting, strenuous exercise, or a very low-carb ketogenic diet—the body must find an alternative fuel source. During this metabolic shift, the liver begins to produce and release ketone bodies into the bloodstream. These water-soluble molecules can cross the blood-brain barrier, which fatty acids cannot, and be utilized by the brain for energy.

The Process of Ketogenesis

Fatty Acid Release: When insulin levels are low, fat cells release stored triglycerides, which are broken down into fatty acids and glycerol.
Liver Processing: These fatty acids travel to the liver, where they undergo beta-oxidation to produce a molecule called acetyl-CoA.
Ketone Body Formation: The liver, unable to fully process the excess acetyl-CoA through the citric acid cycle due to low oxaloacetate levels, converts it into ketone bodies in a process called ketogenesis.
Distribution: The liver releases the ketone bodies—primarily acetoacetate (AcAc) and beta-hydroxybutyrate (BHB)—into the bloodstream for distribution to other tissues, including the brain.
Brain Utilization: Once in the brain, neurons and other brain cells can take up the ketone bodies and convert them back into acetyl-CoA to be used in the citric acid cycle for ATP generation.

The Primary Ketone Bodies

There are three main types of ketone bodies produced during ketosis, two of which are primarily used by the brain for energy:

Beta-hydroxybutyrate (BHB): The most abundant ketone body in circulation. It is readily used for energy by the brain and other tissues.
Acetoacetate (AcAc): Another primary ketone body that the brain can convert to energy. It can also spontaneously decarboxylate into acetone.
Acetone (ACE): A breakdown product of acetoacetate, acetone has minimal metabolic value and is often exhaled, giving a characteristic fruity smell to the breath during ketosis.

Ketone Metabolism vs. Glucose Metabolism in the Brain


Feature	Glucose Metabolism	Ketone Metabolism
Primary Source	Dietary carbohydrates	Fatty acids from stored fat
Location of Production	Digested in the body, primarily stored in liver as glycogen	Produced in the liver via ketogenesis
Dependence on Insulin	Regulated by insulin	Occurs when insulin levels are low
Efficiency	Lower ATP yield per carbon than ketones.	Higher ATP yield per carbon, considered a "cleaner" fuel.
Reactive Oxygen Species (ROS)	Higher production of ROS.	Lower production of ROS.
Timeline for Utilization	Immediate use during normal fed state.	Requires several days of carbohydrate restriction to adapt.

The Neuroprotective Benefits of Ketosis

Beyond simply serving as an alternative fuel, ketones have demonstrated several neuroprotective properties. This is why therapies involving ketogenic diets are being investigated for various neurological conditions, including epilepsy, Alzheimer's disease, and traumatic brain injury. Some of the proposed benefits include:

Reducing Inflammation: Ketone bodies, particularly BHB, can inhibit the NLRP3 inflammasome, a multiprotein complex associated with inflammation in the brain.
Enhanced Antioxidant Defenses: Ketosis can lead to an increase in the NAD+/NADH ratio, improving mitochondrial function and reducing oxidative stress, which contributes to neurodegeneration.
Modulating Neurotransmitters: Ketone bodies can influence the balance between excitatory and inhibitory neurotransmitters, such as by increasing the production of GABA, an inhibitory neurotransmitter.
Increased Brain-Derived Neurotrophic Factor (BDNF): BHB can increase the expression of BDNF, a protein crucial for neuronal survival and growth.

Conclusion

When the body's carbohydrate supply is exhausted, the brain demonstrates an incredible metabolic flexibility by switching its primary fuel source to ketone bodies. This state of ketosis, induced during fasting or by a very low-carbohydrate diet, is a powerful survival mechanism with significant implications for neurological health. While glucose remains the brain's go-to fuel, the ability to effectively use ketones not only meets energy demands but also confers neuroprotective benefits that are the subject of ongoing scientific and clinical research. The transition from carbohydrate-based energy to ketone-based energy highlights the body's remarkable adaptability and resilience.

The Therapeutic Role of Ketogenic Diet in Neurological Diseases - MDPI

Frequently Asked Questions

The brain cannot directly use fatty acids for fuel because most fatty acids cannot efficiently cross the blood-brain barrier, which protects the brain from foreign substances. Ketone bodies, which are water-soluble, can cross this barrier.

The process is called ketosis. When carbohydrate intake is very low, the body depletes its glycogen stores and begins to break down fat for energy, producing and using ketone bodies for fuel.

Yes, even during deep ketosis, some parts of the brain still require a small amount of glucose. The body produces this necessary glucose through a process called gluconeogenesis, which converts amino acids or glycerol into glucose in the liver.

The time it takes for the brain to fully adapt to using ketones as its primary fuel source can vary. Studies show a significant shift in metabolism begins after just a few days of carbohydrate restriction or fasting, with ketone utilization increasing over several weeks.

No, ketosis is not the same as ketoacidosis. Ketosis is a normal and harmless metabolic state characterized by elevated but controlled levels of ketones. Ketoacidosis, a dangerous and potentially fatal condition, occurs primarily in uncontrolled Type 1 diabetes and involves dangerously high levels of ketones and blood glucose.

Ketosis can also be triggered by following a ketogenic diet, a very low-carbohydrate, high-fat eating plan. Intense, prolonged exercise can also induce a temporary state of ketosis.

The three main ketone bodies are beta-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone. The brain primarily uses BHB and AcAc for energy.