Table of contents
Starting a keto diet and making sense of all the terminology can be overwhelming at the best of times. So we’ve created a simple overview of the process and the various steps required to reach ketosis.
By the end of this article you should understand what the keto diet is, what being in ketosis really means and how the body reaches this state.
Summary:
- The keto diet involves consuming very low carbohydrates in order initiate ketogenesis
- Ketogenesis is the process by which fatty acids are converted into ketone bodies
- Ketone bodies are converted to acetyl-CoA in order to produce ATP
- A sufficiently high level of ketones circulating in the body is referred to as a state of ketosis
- Diabetic ketoacidosis is a serious complication of diabetes, in which ketone levels reach dangerous levels
What is the keto diet?
The keto diet is a form of eating in which individuals consume very few carbohydrates (mostly from non-starchy vegetables) and instead focus on moderate amounts of protein and high-fat intake[1].
The objective of the diet is to switch the primary body fuel source away from glucose, which is the body’s preferred energy source when carbohydrates are ingested.
By making carbohydrates a negligible component of your diet, your body undergoes a process called ketogenesis, which produces ketone bodies[1][2].
Ketone bodies are an alternative form of energy for the body, and can cross the blood-brain barrier[2].
This means ketones can supply almost all of the body’s energy requirements, including supplying the brain and can therefore be a near total replacement for glucose.
What is Ketogenesis and when does it occur?
Overview
Ketogenesis is a biochemical process that is responsible for the synthesis of ketone bodies[2].
In a typical moderate-high carbohydrate diet, the primary biochemical process for converting glucose to free energy is glycolysis.
When the body is well-fed with carbohydrates, small amounts of ketogenesis occur, resulting in the production of low levels of ketones[2][3].
However, these are very much an accessory to the primary utilisation of glucose. When carbohydrate intake is drastically reduced however, the traditional glycolysis pathway is inhibited[2].
Instead the body looks to convert readily available glycogen stores into free energy, that is, making it available for cellular metabolism. This occurs through the biochemical pathway glycogenolysis, in which stored glycogen in the liver and the muscles is converted into glucose.
When glycogen stores have been depleted, the body then focusses on endogenous production of glucose through a process called gluconeogenesis.
During this process, glucose is produced from lactic acid, glycerol and the ‘keto’ amino acids; alanine and glutamine[1].
So now you’re no longer eating carbs, your glycogen reserves are depleted and your body is struggling to get all the energy requirements from gluconeogenesis.
This is where ketogenesis is significantly upregulated.
Mechanism of action
Ketogenesis occurs primarily in the mitochondria of liver cells and during the process, fatty acids are broken down to produce the ketones acetoacetate, β-hydroxybutyrate and acetone[1][2].
Step 1:
The first step in the process is the movement of fatty acids into the mitochondria, and this is facilitated by an enzyme called carnitine palmitoyltransferase (CPT-1)[2].
Step 2:
Once in the mitochondria, the fatty acids are broken down into acetyl coenzyme A (CoA) via a process called β-oxidation[2][4].
Step 3:
Following this, the acetyl CoA is converted into acetoacetyl-CoA, through the action of the enzyme acetyl coenzyme A acetyltransferase (ACAT) (also known as thiolase). Two molecules of acetyl CoA are required for every molecule of acetoacetyl-CoA produced[2].
Step 4:
Once acetoacetyl-CoA is synthesised, it must be converted into the intermediate HMG-CoA (β-Hydroxy β-methylglutaryl-CoA), through the action of the enzyme HMG-CoA synthase[2][5].
The final step to create the ketone acetoacetate is via the action of the enzyme HMG-CoA lyase.
Once the ketone acetoacetate is produced, it may be further converted to the ketones acetone and β-hydroxybutyrate through the action of the enzyme β-hydroxybutyrate dehydrogenase (acetoacetate can also be decarboxylated into acetone)[2][5].
The primary energy comes from acetoacetate and β-hydroxybutyrate, although when levels acetone are high enough, they can be metabolised to produce ATP via the propylene glycol pathway[6][7].
Regulators of Ketogenesis
Ketogenesis is peripherally regulated by a number of hormones, of which glucagon, cortisol, thyroid hormones, and catecholamines play a role in its up-regulation.
This upregulation happens through the increased breakdown of fatty acids, the starting molecules of ketogenesis[2][8][9].
The main regulator of ketogenesis is however insulin. Insulin impacts numerous enzymes in the ketogenesis process and a low state of insulin up-regulates ketogenesis by increasing[2][8];
- Free fatty acids (FFAs) through inhibition of hormone-sensitive lipase
- Uptake of FFAs into hepatic mitochondria, due to disinhibition of CPT1
- Production of ketone bodies due to increased HMG-CoA activity
Insulin is the primary hormone that regulates ketogenesis, and when insulin levels are high, ketogenesis is suppressed in favour of glycolysis.
What is ketolysis?
So ketogenesis leads to the production 3 types of ketones produced in the liver, and this process is regulated by several enzymes.
But what happens when these ketones leave the liver and how do they supply other body tissues with energy?
Ketolysis is the biochemical process which converts ketone bodies into energy that can be used to fuel cellular metabolism[7].
Upon leaving the liver and entering the mitochondria of body cells, acetoacetate is converted back to acetoacetyl-CoA via the enzyme succinyl CoA-oxoacid transferase (SCOT) [2][7].
This acetoacetyl-CoA is then converted to acetyl-CoA via the enzyme methylacetoacetyl CoA thiolase (MAT), which cleaves the an acetyl group.
The newly created acetyl-CoA subsequently enters the citric acid cycle, which after undergoing oxidative phosphorylation, produces 22 ATP per molecule[2].
The ketone acetone is usually excreted as it cannot be converted back to acetyl-CoA, although it can undergo metabolism via a different pathway to produce energy[6][8].
What is ketosis?
Physiological Ketosis
Ketosis is a physiological state, characterised by higher levels of circulating ketones[6][7].
When the body undergoes a prolonged period of fasting or severely restricted carbohydrates, ketones become the primary molecule for the production of energy.
Ultimately, achieving and maintaining physiological ketosis is the objective of the Keto diet.
By keeping carbohydrates low, it ensures the body is in a state of ketosis, which leads to a whole host of health benefits, including significant weight loss[5][7].
Diabetes-related ketoacidosis (DKA)
Diabetic ketoacidosis is different from normal physiological ketosis in that it occurs when the body produces too many ketones[7][10][11].
This dangerous body state occurs in people with diabetes, when their bodies produces insufficient insulin, resulting in a severe shortage. It is a complication of diabetes and mostly occurs in people with type 1 diabetes[7][11]. Find more information here.
Pulling it all together
A number of biochemical reactions need to take place in order to produce sufficient ketones to supply the body’s energy needs. The production of these ketones is the result of the biochemical process, ketogenesis, and these ketones then under ketolysis in order to enter the citric acid cycle and produce energy for body cells.
