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The Biochemistry of Fat Burning

You've just eaten some fat. This fat is easily able to cross into the cells of the digestive tract, because fats are able to do this (once they are in fatty acid form at least). However, the body doesn’t want a wad of fat just passing straight through the digestive tract and into circulation, as fat has a tendency to clump up together and this would be pretty catastrophic for a “plumbing” system.

The body has evolved to firstly clump fatty acids into micellar form by complexing them with bile acids, and then as we have discussed in previous lessons, we also transport dietary fats into the lymphatic system before they enter the circulatory system. But to provide a further line of defence against those fats just clumping together and clogging up the lymphatic or cardiovascular system, the cells of the digestive tract also package the dietary fats up into chylomicrons. To do this, the micelles are absorbed into the cells of the digestive tract, the fatty acids are then resynthesised into triglycerides (which the digestive enzymes just broke them out of), and then the endoplasmic reticulum of the digestive tract cells create a chylomicron package to transport these fats (triglycerides, cholesterol and fat-soluble vitamins) into the lymphatic system.

It is important to note, that the chylomicrons are actually in the same family as LDL and HDL. Chylomicrons are sometimes called ultra-low-density lipoproteins (ULDLs). The chylomicrons pass through the lymphatic system before entering the circulatory system, bypassing the first pass through the liver that other nutrients get.

The cells of the body, notably the fat cells, are able to bind these chylomicrons, and then partially digest them. This liberates the glycerol from the fatty acids, and these are absorbed by the fat cells. The glycerol and chylomicron remnants are then transported to the liver to be dealt with (the glycerol is important to remember for later).

Now, let’s assume we are in the fed state (you just ate after all), assuming your overall energy balance is either neutral or positive (i.e. you are eating enough or more than enough), the fatty acids that you just ate are generally going to be stored for later use. The vast majority of the fats are absorbed by fat cells, and they serve as a storage site for these fats for future use. This is a very beneficial set-up because you don’t want cells that have a more dynamic functional role to play, to be filled up with fats. Just like you wouldn’t want your workspace cluttered up with a lot of unwanted stuff, cells like your muscle or heart cells don’t want a load of fat stored in them when they are trying to actually do their job. So the fat cells serve to store the fats for longer-term use.

Now, the fats that have just been absorbed are in free fatty acid form, which isn’t ideal from the perspective of storage, so they are once again resynthesised into triglyceride form (so yes, you ate them in triglyceride form, broke them out of it to get it into the gut cells, where they remade them to triglyceride form and packaged them in chylomicrons, and you broke them out of triglyceride form to get them into the fat cell, where you then remade them into triglyceride form again). The glycerol backbone used to resynthesise these triglycerides is derived from glycolysis (the fat cell also uses glycolysis for energy requirements). Fat tissue (and other cells, mainly the liver) is also able to make fatty acids from glucose (well technically, the fatty acids are made from acetyl-CoA derived from citrate that has been removed from the TCA cycle because there was excess TCA cycle activity due to excess glycolysis).

All you really need to know is that fatty acids can be made from glucose (or amino acids) in fat cells, but not all the fatty acids can be made (thus we still have essential fatty acids we need to consume in the diet). This is important to know, because you will often see people claim that if you don’t eat any fat, you can’t increase your fat stores, and this is simply not the case. (It is also interesting to note that we can’t do the reverse, and create carbohydrates from fatty acids).

As we noted above, the chylomicron remnants and the glycerol that aren’t absorbed by the fat cell are sent to the liver. The liver is able to convert that glycerol into glucose via gluconeogenesis, but assuming an overfed state or simply the liver glycogen stores being full, the liver will start increasing fatty acid production. These fatty acids are then combined with glycerol to form triglycerides, and only in the liver, these cells are able to be packaged up and sent out to the rest of the body. So while other cells can make fatty acids, it is only the liver that can meaningfully distribute those fatty acids around the body. All cells need fats, so the liver plays an incredibly vital role here (along with its many other incredibly vital roles).

The interesting thing is that you have likely already heard about the system that is used to distribute these triglycerides around the body, and it plays a role in the development of heart disease. The liver packages these triglycerides (and other lipids like cholesterol) into packages called very low-density lipoproteins (VLDLs). These VLDLs are then pumped into the blood and are treated much the same way those chylomicrons we discussed earlier (remember, they are also called ultra low-density lipoproteins!). Once the VLDLs are processed, they become intermediate-density lipoproteins (IDL), which are either re-processed by the liver or undergo further triglyceride removal by fat cells or other tissues and become low-density lipoproteins (LDLs). These LDLs are rich in cholesterol, and play a causative role in the development of heart disease. LDL is required to transport cholesterol around the body, so it isn’t necessarily a bad molecule, however, too much LDL can be bad.

Now, we have been in the fed state, and your body has been either creating and/or storing these fats away for future use. Well, the future is now. Glucose levels have fallen, the body needs energy, and you have a large store of energy in the form of triglycerides in your fat cells. The benefit of storing fat versus glycogen is that it is much more easily packed into the cells, it doesn’t pull in a lot of water or oxygen while storing it, and it is also incredibly high energy when you compare it on a gram per gram basis. To use the energy we have stored in the triglycerides, we need to first break them back down into free fatty acids. This occurs when a chylomicron or VLDL is metabolised by fat cells, and the released fatty acids can be transported into the cell and used for energy in that form, or if they have been stored, lipase enzymes break the triglycerides back down into free fatty acids. This process is known as lipolysis. The liberated free fatty acids are either used by the fat cells for energy, or they are pushed into the bloodstream where they are transported to other tissues that need them by albumin. The fatty acids are then transported into the cells that need them by specific transporters, and once inside the cell, the fatty acids are “activated” by an enzymatic reaction that “joins” the fatty acid with ATP to give a fatty acyl adenylate (and inorganic pyrophosphate), which combines with free coenzyme A and becomes acyl-CoA and AMP. Depending on the length of the fatty acid portion of this acyl-CoA, it is either transported into the mitochondria by the carnitine shuttle (for long chains) or by simple diffusion (short chains).

Once inside the mitochondria, the real magic happens. Beta oxidation is the process by which the fatty acid portion of the acyl-CoA molecule is cut into a series of two-carbon units, which are then combined with co-enzyme A to form acetyl CoA. This acetyl CoA is then fed into the TCA cycle, just like the acetyl CoAs were when we discussed glycolysis, and the products then go on to create ATP in the electron transport chain.

Now, of note is, this system really only describes what happens to even chain fatty acids (as it cuts them up into units of 2 carbons), and it also only works for saturated fats. For odd-numbered saturated fats, the process stays the same except the final product produced is propionyl-CoA and acetyl CoA. The propionyl-CoA undergoes a rather complex enzymatic process, which you definitely don’t need to know, and ultimately becomes succinyl-CoA. This succinyl-CoA is an intermediate of the TCA cycle, and thus it is able to just slot into the cycle in its own right, rather than needing to complex with another molecule (like acetyl CoA and oxaloacetate complex together). No real net energy is derived from it slotting in at this point, but it does serve a purpose in restocking the other intermediates (such as oxaloacetate), among other purposes (such as creating other molecules with the TCA cycle intermediates).

Unsaturated fats are a little different because they can’t be neatly cut into units with 2 carbons, due to the fact they have a carbon that is saturated with hydrogens (i.e. there is a double bond in there somewhere). So a slightly different process occurs, and two other enzymes are required to convert the unsaturated fat into a type of fat that can be broken down into the 2 carbon units. Once they are converted, the exact same process of beta-oxidation as before occurs.

Beta oxidation does not directly utilise oxygen, but it is an inherently aerobic process. Unlike with glycolysis, there is no way to shuttle the products off to other molecules (pyruvate to lactate) that can be used for energy later, so if are not able to use the electron transport chain, you aren’t able to get much energy at all from beta-oxidation. The electron transport chain needs oxygen to yield energy, thus beta-oxidation needs oxygen to actually yield energy.

The way fats are metabolised via beta-oxidation is also why you can’t make carbohydrates from fatty acids, because the acetyl-CoA can’t be converted back to pyruvate (we lack the ability to do this). It is also important to understand that you do actually need some level of carbohydrates to make the burning of fats work effectively, because without sufficient pyruvate being fed into the system, oxaloacetate levels decline and thus the acetyl CoAs coming from beta-oxidation don’t have enough to complex with to form citrate, and thus, the cycle can’t work. However, alanine (an amino acid) can be used to create pyruvate, which can then be used to create oxaloacetate. That alanine is generally derived from protein breakdown, and this is one of the many reasons why when dieting, we want to keep carbohydrate levels adequate. Keeping carbohydrates in the diet helps to prevent muscle protein breakdown, it ensures there isn’t an oxaloacetate shortage, and it facilitates the burning of fats for energy. Odd-numbered fats are also able to regenerate oxaloacetate, via their conversion to succinyl-CoA.

However, that isn’t the whole story. If protein intake is low or amino acids aren’t meaningfully being contributed to the TCA cycle (i.e. proteins aren’t being broken down), and glucose also isn’t meaningfully contributing to the TCA cycle, the body does have another fallback. When glucose levels are low, oxaloacetate can be used to produce glucose via gluconeogenesis and assuming there are no easily utilised precursors for oxaloacetate (i.e. pyruvate), the acetyl-CoA can be used in a process called ketogenesis, and form ketones which can be used for energy (some amino acids are able to fuel ketogenesis).

Ketogenesis occurs in the mitochondria of liver cells predominantly. Two acetyl-CoA molecules combine to form acetoacetyl-CoA, which then briefly combines (via enzyme action) with another acetyl-CoA to form hydroxy-β-methylglutaryl-CoA, which then goes on to form the ketone body acetoacetate (via enzyme action). Acetoacetate can also be converted to D-β-hydroxybutyrate (via enzyme action) which is another ketone. Acetoacetate can also spontaneously degrade into acetone and carbon dioxide (acetone is the same stuff people use to remove nail polish, and it has a very distinct smell).

These ketone bodies aren’t actually able to be used by the liver (the liver lacks the enzymes to break down ketones) and are shipped off to be used by other organs for use (namely the muscle and the brain). In other tissues, the ketones can be broken down to their building blocks of acetyl-CoA molecules, and these can be used in the TCA cycle and electron transport chain, thus generating energy.

It should be noted that in (predominantly type 1) diabetics, insulin levels may be incredibly low, despite the presence of glucose in the blood. The liver increases the production of glucose (gluconeogenesis) because the cells aren’t receiving glucose (because insulin is required to get it into the cells), which causes the body to urinate out the glucose, which also brings along a variety of electrolytes and an excessive amount of water.  Ketone production also ramps up. The increased production of ketones causes the blood to become acidic, and combined with the loss of electrolytes and water, a condition known as diabetic ketoacidosis develops. This is potentially fatal, although it can be managed with medical intervention.

So that is fat metabolism, and as you can see, this stuff does get a little bit complex quite quickly. As I have mentioned a few times, you really don’t need to memorise this stuff, and you just need to become familiar with the general overview of it all. Of course, the more you do understand, the better informed you are, but you really don’t need to understand all of this stuff to be able to help other people with their nutrition or to help yourself. But we aren’t finished with metabolism yet, as we have to discuss protein.

To learn more, see further information about the Triage Nutrition Certification below.