In this Metabolic Classroom lesson, Dr. Ben Bikman explores one of the most important shifts in metabolic science over the past decade: the discovery that ketones are not just an alternative fuel, but powerful signaling molecules. You’ll learn how beta-hydroxybutyrate communicates with cells to reduce inflammation, protect mitochondria, and influence gene expression—and why this changes how we think about fasting, ketogenic diets, and metabolic health.
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Ketones Are Not Just Fuel
For decades, ketones were misunderstood.
Early biochemistry textbooks treated them as metabolic waste. Later, they were rebranded as a backup fuel — something the body used only when glucose was scarce. But modern metabolic research has revealed a much more powerful truth:
Ketones, specifically beta-hydroxybutyrate (BHB), are not just fuel molecules. They are signaling molecules that act like hormones.
This discovery has fundamentally changed how we understand fasting, ketogenic diets, exercise, inflammation, and mitochondrial health.
Ketones Have a Dual Identity
Most molecules in the body fall neatly into one category:
- Nutrients provide energy
- Hormones send signals
Ketones break this rule.
Beta-hydroxybutyrate does both.
On one hand, BHB is an efficient energy source, converted into acetyl-CoA and used by mitochondria to generate ATP. On the other, it binds to receptors, alters gene expression, and directly influences inflammation and cellular stress resistance.
This dual role is exceptionally rare in biology.
When Do Ketones Rise?
BHB is produced primarily in the liver when fatty acids are oxidized at high rates. This happens during:
- Fasting or time-restricted eating
- Prolonged exercise
- A well-formulated ketogenic diet
At modest concentrations — typically between 1–2 millimolar — BHB begins to exert signaling effects that go far beyond energy production.
Ketones as Anti-Inflammatory Signals
One of the most important signaling roles of BHB is its ability to reduce inflammation.
BHB can activate specific cell-surface receptors on immune cells, shifting them toward less inflammatory, more protective states. In addition, BHB directly inhibits the NLRP3 inflammasome, a key inflammatory complex responsible for producing interleukin-1 beta (IL-1β).
IL-1β plays a central role in chronic diseases such as:
- Type 2 diabetes
- Atherosclerosis
- Alzheimer’s disease
- Autoimmune and autoinflammatory disorders
By dampening this inflammatory pathway, ketones help protect tissues from inflammation-driven damage — particularly in the brain, heart, and metabolic organs.
Ketones and Gene Expression
Ketone signaling doesn’t stop at the cell surface.
Beta-hydroxybutyrate also enters the nucleus, where it influences epigenetics — the way genes are turned on or off.
BHB inhibits specific histone deacetylases (HDACs), enzymes that normally suppress gene expression. When HDACs are inhibited, genes involved in antioxidant defense and cellular stress resistance become more active.
The result?
Cells become better prepared to handle oxidative stress, one of the primary drivers of aging and chronic disease.
Ketones and Mitochondrial Protection
Mitochondria are both energy producers and vulnerability points. They generate ATP, but they also produce reactive oxygen species and are highly sensitive to inflammation.
Ketone signaling helps mitochondria in several ways:
- Provides a highly efficient fuel source
- Reduces inflammation that damages mitochondrial function
- Enhances antioxidant gene expression
- Improves overall metabolic resilience
Rather than simply “burning ketones for energy,” cells use ketones as a signal to protect their energy systems.
Why This Changes How We Think About Metabolism
The idea that ketones act like hormones reframes metabolic health entirely.
When ketones rise, the body receives a coordinated message:
- Glucose is limited, but fuel is available
- Inflammation should be reduced
- Stress resistance should increase
- Long-term cellular protection should be prioritized
This helps explain why fasting, exercise, and ketogenic diets often improve markers of metabolic health — not just because of calorie balance, but because of cellular signaling.
The Takeaway
Ketones are not metabolic leftovers.
They are not merely backup fuel.
Beta-hydroxybutyrate is a powerful signaling molecule that connects how we eat and move to inflammation, gene expression, and mitochondrial health.
Understanding ketones this way moves us beyond diet trends and into true metabolic science — where fuel and signaling work together to support resilience, longevity, and better health.