Ketosis: The Chemistry of Burning Fat

When you skip breakfast, fast for a day, or follow a very low-carbohydrate diet, your body’s chemistry shifts. Stores of glucose run low, fat breakdown speeds up, and the liver starts producing small, water-soluble fuel molecules called ketone bodies. This state is ketosis. It’s a normal survival mechanism that has kept humans alive through periods of hunger for as long as our species has existed. It also has a dangerous extreme, ketoacidosis. The chemistry explains both.

The problem ketosis solves

The body stores energy in two main forms:

• Glycogen — a glucose polymer in the liver and muscles. It’s quick to use, but the liver’s supply lasts less than a day without food (see what happens to sugar in your body).
• Fat — triglycerides in fat tissue. Enough, in a lean adult, for weeks of basic needs.

Most tissues, including muscle and the heart, can burn fatty acids directly. The brain can’t use them much at all: long fatty acids don’t cross the blood–brain barrier well, and brain cells aren’t built to oxidise them in large amounts. The brain normally runs on glucose, using around 120 g a day.

When food is short, the liver can make some new glucose (gluconeogenesis), but mostly from amino acids — which means breaking down muscle protein. If the brain relied only on glucose during a long fast, the body would waste away its muscles. Ketone bodies solve this problem: they’re made from fat, they dissolve in blood, and the brain can use them. By the third or fourth day of fasting, ketones can supply more than half of the brain’s energy, greatly reducing the need to break down protein.

Meet the ketone bodies

There are three, all small molecules made from two-carbon acetyl units:

Name	Formula	Notes
Acetoacetate (3-oxobutanoate)	CH₃COCH₂COO⁻	The first one made; a true ketone plus a carboxylate
β-Hydroxybutyrate (3-hydroxybutanoate)	CH₃CH(OH)CH₂COO⁻	The main one in blood; technically not a ketone (it has –OH, not C=O)
Acetone (propanone)	CH₃COCH₃	Formed spontaneously from acetoacetate; breathed out

The name “ketone bodies” is historical, and one of them isn’t strictly a ketone — a nice example of old names outliving the chemistry.

Making ketones in the liver

Step 1: fat breakdown (lipolysis)

When insulin is low and glucagon and adrenaline are high, fat cells break triglycerides into glycerol and fatty acids (see fatty acids). The fatty acids travel in the blood, attached to the protein albumin, to the liver and other tissues.

Step 2: β-oxidation

Inside liver mitochondria, fatty acids are cut into two-carbon acetyl-CoA units, two carbons at a time. A 16-carbon palmitic acid gives eight acetyl-CoA molecules. This process also produces a lot of NADH and FADH₂ (see cofactors and coenzymes).

Step 3: the traffic jam at the Krebs cycle

Normally, acetyl-CoA joins with oxaloacetate to enter the Krebs cycle. But during fasting, the liver is busy making glucose, and it uses oxaloacetate as a starting material for gluconeogenesis. With oxaloacetate in short supply, acetyl-CoA piles up.

Step 4: ketogenesis

The liver channels the excess acetyl-CoA into ketone bodies:

1. Two acetyl-CoA join to form acetoacetyl-CoA.
2. A third acetyl-CoA is added, forming HMG-CoA (the same intermediate involved in cholesterol synthesis — see cholesterol).
3. HMG-CoA is split into acetoacetate and acetyl-CoA.
4. Much of the acetoacetate is reduced by NADH to β-hydroxybutyrate.
5. A little acetoacetate loses CO₂ spontaneously to form acetone.

Here’s a neat twist: the liver makes ketones but can’t use them. It lacks one of the enzymes needed to break them down, so it exports all of them to other tissues.

Using ketones for energy

In the brain, heart and muscles, β-hydroxybutyrate is oxidised back to acetoacetate, which is converted to acetoacetyl-CoA and split into two acetyl-CoA molecules. These enter the Krebs cycle, producing ATP. Effectively, the liver pre-digests fat into a form that travels easily and can be burned by tissues that can’t handle fatty acids directly.

“Keto breath” and acetone

Acetone is volatile (it boils at 56 °C) and isn’t used much by the body, so some of it is breathed out and some passes into urine. That’s why people in ketosis sometimes notice a fruity or nail-polish-remover smell on their breath. Breath-acetone meters and urine test strips (which detect acetoacetate) are used to check for ketosis.

How much is “ketosis”?

Blood ketones (mainly β-hydroxybutyrate) are normally very low — below about 0.5 mmol dm⁻³. Rough ranges:

State	Blood ketones (approx.)
Normal, fed	< 0.5 mmol dm⁻³
Nutritional ketosis (low-carb diet, overnight or longer fast)	0.5–3 mmol dm⁻³
Prolonged fasting (several days)	up to about 5–7 mmol dm⁻³
Diabetic ketoacidosis (DKA)	often > 10 mmol dm⁻³

Ketosis vs ketoacidosis

Here’s where acid–base chemistry comes in. Acetoacetic acid and β-hydroxybutyric acid are carboxylic acids, with pKa values of about 3.6 and 4.7. At blood pH (about 7.4), they’re almost completely ionised, which means each molecule produced has released a hydrogen ion into the blood (see the pH scale explained).

In nutritional ketosis, the amounts are modest. The blood’s buffer systems — especially the hydrogencarbonate buffer — easily absorb the extra H⁺, and blood pH stays normal (see the blood buffer system). Crucially, a small amount of insulin is still being made, which acts as a brake on fat breakdown and stops ketone levels spiralling upward.

In diabetic ketoacidosis (DKA), most often in type 1 diabetes, there’s almost no insulin at all. Without the insulin brake:

• Fat breakdown runs unchecked, flooding the liver with fatty acids.
• The liver produces ketones far faster than tissues can use them.
• Blood glucose also soars, because cells can’t take it up and the liver keeps making more.

Ketone levels climb far beyond nutritional ketosis, the hydrogencarbonate buffer is used up, and blood pH falls — sometimes below 7.0. High glucose also pulls water out through the kidneys, causing severe dehydration. Symptoms include deep, rapid breathing (the body trying to blow off CO₂ to raise pH), vomiting, confusion and the smell of acetone. DKA is a medical emergency, treated with insulin, fluids and careful replacement of potassium.

So the difference isn’t whether ketones are present, but how much and whether insulin is there to keep them in check.

Ketogenic diets

A ketogenic diet is very low in carbohydrate (often under about 50 g a day), moderate in protein and high in fat. It shifts the body into nutritional ketosis. It has a long medical history: since the 1920s it has been used to reduce seizures in some children with epilepsy that doesn’t respond to drugs. It’s also used for weight loss, where results in the long term tend to be similar to other diets that reduce energy intake by the same amount. Anyone with diabetes, kidney disease or other medical conditions should seek medical advice before trying it.

Common misconceptions

• “Ketosis and ketoacidosis are the same.” Nutritional ketosis keeps blood pH normal; ketoacidosis is an uncontrolled acid build-up.
• “The brain can only use glucose.” During fasting, ketones supply a large share of its energy.
• “Ketone bodies are all ketones.” β-Hydroxybutyrate is a hydroxy acid.
• “The liver burns ketones.” The liver makes them but can’t use them.

Key takeaways

• Ketosis is the body’s way of turning fat into a brain-friendly fuel when carbohydrate is scarce.
• The liver converts fatty acids → acetyl-CoA → acetoacetate → β-hydroxybutyrate (and some acetone).
• Ketones are used by the brain, heart and muscles, sparing protein during fasting.
• Ketone bodies are acids; buffers cope in nutritional ketosis, but without insulin, diabetic ketoacidosis can lower blood pH dangerously.

For the other side of the energy story, see lipids explained and what happens chemically when you exercise.