Ketosis is a normal metabolic process. When the body does not have enough glucose for energy and when glycogen stores are depleted, it burns stored fats instead. There are 2 ways to get into ketosis:

  1. Following the keto diet or other low-carb diets.
  2. Fasting or intermittent fasting.

Ketones role in the body were discovered over 100 years ago when scientists detected acetone in the breath which increased with strenuous exercise or fasting.

What is a fat?

There are many different kinds of fats, but each is a variation of the same chemical structure. All fats are derivatives of fatty acids and glycerol, called glycerides. Many fats are triglycerides which are more complex glycerides based on the 3 carbons of glycerol. As you can see below, the body simply removes 3 water molecules to create the triglyceride.

Adipose tissue, or fat, is an anatomical term for loose connective tissue composed of adipocytes. Its main role is to store energy in the form of fat, although it also cushions and insulates the body. Brown adipose tissue is found in almost all mammals. White adipocytes contain a single lipid droplet, brown adipocytes contain numerous smaller droplets and a much higher number of (iron-containing) mitochondria, which gives brown adipose tissue its brown appearance.

Breaking fats to give energy

There is so much nonsense on the Internet regarding ketosis and ketones. The body is quite capable of burning fats without the need to produce ketones, fatty acids are broken down throughout the body. So let's take a step back. All fats in the body are glycerides (glyceride = glycerol + fatty acids). When a fat breaks down, a long chain of carbon with an acidic part at the end is produced which is called a fatty acid. Fatty acids are bound to the protein albumin when they are transported in the blood. Fatty acids are ultimately oxidized by β-oxidation into acetyl-CoA (Coenzyme A combines with the fatty acid to produce the activated version).

Beta oxidation is a metabolic process involving multiple steps by which fatty acid molecules are broken down to produce energy. It happens in the mitochondria in our cells. Beta oxidation consists of breaking down long fatty acids (that have been converted to acyl-CoA chains) into progressively smaller fatty acetyl-CoA chains. This reaction releases a smaller acetyl-CoA molecule and the compounds called FADH2 and NADH. These three can then enter another metabolic process called citric acid cycle or Krebs cycle, in which ATP is produced to be used as energy. Beta oxidation goes on until the acetyl-CoA chain has been completely broken down (Imagine a long strip of paper being progressively cut by scissors).

The glycerol that is released from triglycerides after lipolysis directly enters the glycolysis pathway (Glycolysis is a series of reactions that and extract energy from glucose by splitting it into two three-carbon molecules called pyruvates). Because one triglyceride molecule yields three fatty acid molecules with as much as 16 or more carbons in each one, fat molecules yield lots of energy. When glucose levels are low, triglycerides can be converted into acetyl CoA molecules and used to generate ATP through aerobic respiration.

The liver turns acetyl CoA into ketones! (AcAc, 3HB and Acetone)

The cells of the liver perform the same function in that they can convert fatty acids into acetyl CoA. This is what happens to the acetyl CoA in the liver:

  1. Two acetyl CoA molecules are combined (condensed) into Acetoacetyl CoA.
  2. Another acetyl CoA is added to produce HMG-CoA.
  3. The HMG-CoA degrades down to acetylacetate (AcAc) which is a ketone body (HMG-CoA can also be reduced in the mevalonate cycle to create cholesterol. Cholesterol is needed for testosterone production and this is why testosterone production is boosted with a fatty diet and a state of ketosis).
  4. AcAc can break down into 3HB (this is reversible).
  5. AcAc can break down into Acetone. Acetone production is minor compared to the other 2 ketones.

For complete combustion of fatty acids to ATP plus carbon dioxide plus water, glucose is required to keep the citric acid cycle running. If glucose is not available, acetyl coenzyme A is converted to molecules called ketone bodies. The fat-derived energy (ketone bodies) generated in the liver enter the blood stream and are used by other organs, such as the brain, heart, kidney cortex and skeletal muscle. Ketone bodies are particularly important for the brain which has no other substantial non-glucose-derived energy source. The two main ketone bodies are acetoacetate (AcAc), 3-hydroxybutyrate (3HB) and acetone. Ketone bodies are always present in the blood and their levels increase during fasting and prolonged exercise. After an over-night fast, ketone bodies supply 2–6% of the body's energy requirements, while they supply 30–40% of the energy needs after a 3-day fast. When they build up in the blood they spill over into the urine. The presence of elevated ketone bodies in the blood is termed ketosis and the presence of ketone bodies in the urine is called ketonuria. The body can also rid itself of acetone through the lungs which gives the breath a fruity smell.

All fat within the body has a glycerol backbone within the molecules, your body can break down fats into glycerol which can be broken down further into glycogen and glucose. Even if your body is fasting for days, it is still able to produce glucose from fat. We can survive without eating carbs and just ingesting protein and fats. Your body can make as much glucose as it needs, just by guzzling fat, whether it be stored or ingested. Your brain and cognitive functions are quite capable of running with a zero carbohydrate intake.

Ketolysis turns the ketones into fuel

Ketolysis is the process by which ketone bodies produced in the liver are converted (in non-liver tissues), into acetyl CoA which, on complete oxidation via the tricarboxylic acid cycle and oxidative phosphorylation, provides energy. Ketolysis occurs in the mitochondria of many organs.

Much of human history involves a search for food, with long periods of prolonged hunger when food was not available. Human metabolism thus developed mechanisms to cope with starvation. The use of stored fat reserves and their conversion to ketone bodies as a source of energy surely played a dominant role in the survival of the human species. The ability of ketone bodies to maintain life through their capacity to supply fuels, maintain electrolyte conservation, promote gluconeogenesis, and maintain acid–base balance during starvation has diminished in significance since humans now graze all day on simple carbs.

Your brain requires glucose as a fuel. Glucose is virtually the sole fuel for the human brain, except during ketosis. The brain lacks fuel stores and hence requires a continuous supply of glucose. It consumes about 120g daily, which corresponds to an energy input of about 420 calories.  The backup is ketone bodies that the liver derives primarily from fatty acids in your diet or body fat.

Insulin Prevents Lipolysis

Lipogenesis is the process that converts sugars to fats, which are subsequently deposited and stored in fat tissue. Lipolysis is the process of fat breakdown, typically to generate energy. These two metabolic activities are controlled by hormones. Insulin is particularly important in fat metabolism and lipolysis.

When your blood sugar level rises, insulin drives glucose into your cells to regulate blood sugar. But it also inhibits the secretion of glucagon, the pancreas releases glucagon when the concentration of glucose in the bloodstream falls too low. Glucagon causes the liver to convert stored glycogen into glucose. When insulin is present, you cannot burn fat..... so insulin promotes lipogenesis and effectively prevents lipolysis.

Intermittent fasting also encourages the state of ketosis because the body is not being inundated with constant sugar hits and insulin spikes. If you want to understand fat burning and ketosis, you need some appreciation of how fats degrades into ketones within the body.

When your blood has a low concentration of glucose for a sufficient period of time, the fat production process is reversed. Your pancreas releases a protein and glycogen is depleted. Other hormones (epinephrine, cortisol, testosterone, etc) are introduced into your system, and lipisd in the white fat cells (that house our triglycerides) are pulled from the fat cells and converted into Acetyl Co-A, which is the key precursor for the process your body uses to generate “energy” (i.e. ATP) for your cells.

Triglycerides and cholesterol are fats that come from your diet or are made in your body. Triglycerides are stored mainly within lipid droplets in cells of your fatty tissue, also called adipose tissue. However, triglycerides can inappropriately accumulate in organs such as your liver and muscle. Cholesterol is also stored within lipid droplets in your cells, but its primary function is to contribute to the structure of the outer membrane of every cell in your body. Triglycerides can be mobilized from storage sites and burned for fuel, whereas cholesterol is metabolized to bile acids, sex hormones and vitamin D.

Triglyceride Mobilization

Triglycerides are primarily mobilized through stimulation of cells in your adipose tissue by hormones, which include epinephrine, commonly known as adrenaline. Hormone stimulation causes the breakdown of triglycerides to fatty acids, which are released into your blood and picked up by tissues such as your heart, muscles and liver. Triglycerides are usually broken down when there is a relative deficiency of glucose reaching your body’s tissues and energy is needed. This can occur during overnight fasting, during prolonged intense exercise or if you have diabetes and glucose uptake into your tissues is not functioning properly.

Ketone bodies can be anti-inflammatory. Some kinds of cancer cells are unable to useketone bodies, as they do not have the necessary enzymes to engage in ketolysis. It has been proposed that actively engage in behaviors that promote ketogenesis and could help manage the effects of some cancers.

Various Diets

Ketogenic diets are high fat and very low carbohydrate diets. Nutritional ketosis (NK) comes from dieting. Ketosis can also happen during fasting periods, which is known as fasting ketosis (FK). There are problems with the nutritional ketosis only approach:

  1. NK requires calorie counting to ensure you are eating very little carbs and tons of fat.
  2. The Keto diet is trendy and all the rage at the moment.
  3. NK requires a BIG change in eating patterns and it's very easy get quick results and have them reversed by eating carbs again.
  4. The standard model for the keto diet is only 5% carbohydrate which equates to 100-150 calories per day. This is very hard to achieve over time. 1g of carbs deliver about 4 calories, so we are talking less than a small snickers bar a day or about 5 after eight mints. A diet is only as good as a persons ability to stick with it.
  5. Metabolism can slow down (your body thinks it's starving and will slow things down accordingly).
  6. The almost total avoidance of carbs on keto diets can cause issues with hormonal health. Studies have shown that the thyroid in particular can suffer.
  7. NK is similar the the Atkins diet which was once all the rage.
  8. People find it hard to maintain muscle mass on a keto diet, let alone add muscle mass.
  9. NK generates oxygen radicals and cause lipid peroxidation. Lipid peroxidation and the generation of oxygen radicals may play a role in vascular disease in diabetes.