Low carb, keto, fatty acid oxidation, etc., are all being considered the best thing ever.
The more fats your burn the better you’re off right?
It helps you “improve insulin sensitivity”, become “metabolically flexible”, lose fat (you got to burn fat to lose fat right?), etc.
But what if I told you that approach is backwards. I call bullshevik.
What is the goal of becoming metabolically flexible?
To burn both glucose and fat effectively.
Is that achievable on a very low carb, ketogenic diet?
Nope. How do you enjoy your metabolic flexibility with less than 50g of carbs daily? Not a lot right, because you’re not having any carbs!
Some call it physiological glucose sparing, which is correct, but in this state, you don’t magically switch from fat burning to glucose burning. You are actually glucose-intolerant for a few days when you start to eat more carbs because your body needs to adapt again. And if you’re lucky, you re-adapt in a few days, however some peoples’ metabolisms are compromised long term and it takes them months to recover proper metabolic flexibility after a keto diet. That’s not metabolically flexible according to my definition.
So becoming a fat burner is not the best idea in order to become healthy and metabolically flexible.
Before I give the alternative, let’s first discuss why things go wrong.
How the body uses fuel
The body is able to burn glucose, fat, protein and alcohol for energy. Glucose and fat are the main fuel sources, however, at rest, fat is the main fuel source for a few organs, such as the heart and muscles.
The brain uses glucose as energy, and the other organs use a mix between fat and glucose.
Even though the muscles use mostly fat at rest, roughly 90%, it still uses some glucose as well. It’s never either-or. Plus, the amount of glucose burned can go up depending on the amount of dietary carbs consumed.
Glucose oxidation is low on a low carb diet and can be very high on a high carb low fat diet.
You might be surprised to learn this, but muscles don’t count all that much towards total daily energy expenditure.
Muscle tissue contribute approximately 20% to TDEE (total daily energy expenditure) versus 5% for fat tissue (for individuals with about 20% body fat). In fact, the scientific estimation of the metabolic rate of muscle is about 10 to 15 kcal/kg per day, which is approximately 4.5 to 7.0 kcal/lb per day. So if you add another 10kg of muscle (which is actually a lot), you only burn an additional 100-150 calories. Pretty meh right?
On the other hand, your organs are highly metabolically active. It is fascinating to note that the combined energy expenditure of the heart, lungs, kidneys, brain and liver represents approximately 80% of the TDEE. These organs have a metabolic rate that is 15-40 times greater than their equivalent weight of muscle and 50-100 times greater than fat tissue (R). Stress hormones, such as cortisol, are very catabolic to organ tissue whereas your steroids, such as progesterone, DHEA, testosterone, DHT, etc., protect your organs against the catabolic effect of cortisol.
But back to glucose oxidation in muscles. Glucose oxidation is roughly 0.1-0.12g/min at rest (R), which is 6g glucose per hour and 144g per day on a moderate carb diet.
The brain uses about 120-150g glucose per day depending on how much you use your noggin, your muscles use about 144g and your liver can store 100-200g glycogen.
So you can literally eat 400-500g carbs without any of it being converted to fat. Which is actually well in line with studies showing that de novo lipogenesis (DNL) is only appreciably unregulated after eating 500g carbs in OVERFEEDING conditions after 7 days (R). If you eat 500g of carbs while eating at maintenance or slightly over, your body will burn all of it and store none of it.
But I digress.
One last thing that I’d like to mention is that the heart also uses a large amount of fat, 60-80%. Fatty acids, however, are not as efficient as glucose as a source of myocardial energy when viewed in terms of oxygen consumption, since fat oxidation requires more oxygen to produce the equivalent amount of ATP. In heart disease, forcing glucose oxidation by inhibiting fatty acid oxidation improves heart function and survival rate. More on that later.
Let’s summarize this bit
- The body uses both glucose and fat at the same time at all times.
- Total glucose and fat oxidation vary depending on the amounts in the diet.
- Fat loss is the same between a low carb and high carb diet if total protein and calories are kept the same, despite higher insulin and lower lipolysis and fatty acid oxidation (FAO) on a high carb diet.
- You can eat a very large amount of carbs daily and burn it all without becoming insulin resistant or fat.
How fatty acid oxidation works
The origin and storage of fat
Fat can come from the diet (exogenous), fat stores (released by lipolysis) and the conversion of glucose to fat (which is a very small amount).
Unlike glucose, fat doesn’t speed up its own oxidation, so the body has to store the excess rapidly.
Lipolysis is regulated by insulin, so when insulin drops low, then fats are released from the fat stores to be converted to energy.
Lipolysis releases about 2 times as much fat than what can be used through beta-oxidation. The excess is re-esterified and stored in the liver, muscle and fat cells.
Different kinds of fat
There are hundreds of different kinds of fatty acids which are grouped together in 4 classes, namely saturated fat (no double bonds), monounsturated fat (1 double bond), polyunsaturated fat (more than 1 double bond) and transfat.
In these groups, there are many different kinds of fat. For example, saturated fatty acid chain length varies between C3 (propionic acid) all the way up to C40 (tetracontylic acid). The differences in chain length determine what the body will do with it. Medium-chain fatty acids are very quickly oxidized as fuel, whereas longer chain fats, such as stearic acid, are oxidized much slower and are incorporated into cell membranes at a higher level.
How fats are utilized
Fatty acids circulating in the blood are transported into the cytosol of the cell. In the cytosol these fats can undergo peroxisomal beta-oxidation, where it is shortened. Peroxisomal beta-oxidation generates hydrogen peroxide (H2O2) in the process.
Obesity-resistant animals show enhanced peroxisomal β-oxidation metabolism and reduced fat accumulation in visceral adipose tissues (R).
Fats in the cytosol can then enter the mitochondria, where it can then undergo mitochondrial beta-oxidation, which breaks fats down for energy. Mitochondria beta-oxidation generates acetyl-CoA, NADH and FADH2 in the process. The NADH and FADH2 are then used in the electron transport chain to generate ATP.
However, for long chain fats to enter the mitochondria, it has to be transported inside via the carnitine shuttle.
The first step is carnitine palmitoyltransferase-1 (CPT1). CPT1 is located on the outer mitochondrial membrane and transports long-chain fatty acids into mitochondria for β-oxidation.
The rate of fatty acid oxidation is mainly regulated by the concentration of free fatty acids in the blood, the activity of CPT‐I, and the activity of a series of enzymes that catalyze the multiple steps of fatty acid β‐oxidation.
Short and medium-chain fats can enter the mitochondria without CPT1 and be used for beta-oxidation. As a side note, medium-chain fats don’t interfere with glucose oxidation similar to long-chain fats. So if you block CPT1 completely, your body can still shorten long-chain fats into medium-chain fats, which can then enter the mitochondria to be completely broken down by mitochondrial beta-oxidation.
Why fat oxidation is not the key
To lose fat, improve insulin sensitivity or resolve a condition such as fatty liver for example, the general consensus is to increase fatty acid oxidation. This is usually achieved with a low carb diet and/or by supplementing carnitine.
But let’s look at the rate of fatty acid oxidation in fatty liver and diabetes.
Liver fat oxidation is unchanged in NAFLD compared to people with lean livers. On the other hand, whole-body lipid oxidation is increased because of insulin resistance. This data imply that the fatty acid oxidation rate in the liver doesn’t contribute to liver fat content in humans (R).
People with diabetes and obesity also don’t have a decrease in the amount of mitochondrial beta-oxidation compared to their healthy counterparts (they actually have higher beta-oxidation in some cases), however, some of them experience less overall complete beta-oxidation, due to smaller, damaged and fragmented mitochondria. Excess oxidative stress due to chronic overeating on high sugar and high PUFA foods do that.
It was concluded that the reduced FA oxidation in obesity is attributable to decreased muscle mitochondrial content and not intrinsic defects in mitochondrial FA oxidation… The reduced skeletal muscle mitochondrial content with obesity may result from impaired mitochondrial biogenesis.Study
So loading up on carnitine will not do much, because it doesn’t fix the issue of fewer, small, damaged and fragmented mitochondria.
Plus, trying to force fat oxidation will worsen glucose oxidation and insulin sensitivity.
Fatty acid oxidation strongly inhibits glucose and lactate oxidation at the level of pyruvate dehydrogenase (PDH). This inhibition is mediated by the high ratios of NADH/NAD+ and acetyl‐CoA/free CoA induced by fatty acid oxidation, which inhibits flux through PDH.
Why carnitine supplementation sometimes help
To find the answer for this, we’ll look to the heart.
As mentioned above, the heart uses about 60-80% fat and the rest is glucose. This is because fat oxidation requires too much oxygen to generate ATP, which leads to ineffective muscle contraction. The excessive reliance on fatty acid oxidation as a source of energy can increase the oxygen cost of contractility. Forcing or at least restoring glucose oxidation in the heart improves the contraction of the heart muscle.
Carnitine supplementation has been shown to improve heart function, but not by boosting fat oxidation. It actually lowers fat oxidation and boosts glucose oxidation.
This is because carnitine is also used to shuttle acetylcarnitine out of the mitochondria, thus allowing proper glucose oxidation, because acetylcarnitine inhibits proper glucose oxidation.
Carnitine switches energy substrate preference in the heart from fatty acid oxidation to glucose oxidation. Shocker isn’t it?
By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Several studies have indicated that CrAT combats nutrient stress and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase and enhance metabolic flexibility.Reference
Benefits of blocking fatty acid oxidation
Excess fatty acid oxidation is involved in many pathologies and blocking FAO has been shown to be highly beneficial.
Carnitine has clear effects on CPT1, but in many disease states such as insulin resistance, this pathway is excessively active.Reference
Numerous studies have shown that the overexpression of CPTI is tightly associated with tumor progression in breast cancer,52, 53, 54 gastric cancer,55 prostate cancer,25, 50 lung cancer,18 ovarian cancer,56, 57 hepatoma,58 myeloma51 and high grade glioblastoma.Reference
Fatty acid oxidation fuels cancer with ATP and NADPH. NADPH is used to create fatty acids through fatty acid synthase (FAS) and for the synthesis of glutathione. Glutathione protects cancer cells against oxidative stress and death.
CPTI activates FAO and fuels cancer growth via ATP and NADPH production, constituting an essential part of cancer metabolism adaptation.Reference
Blocking FAO is even helpful against tuberculosis.
Mycobacterium tuberculosis (Mtb) is the leading infectious disease killer worldwide. We discovered that intracellular Mtb fails to grow in macrophages in which fatty acid β-oxidation (FAO) is blocked. Macrophages treated with FAO inhibitors rapidly generate a burst of mitochondria-derived reactive oxygen species, which promotes NADPH oxidase recruitment and autophagy to limit the growth of Mtb.Reference
Inhibiting fatty acid oxidation has anti-leukemic effects.
The ability of avocatinB to selectively enhance anti-leukemic effects of AraC in the presence of BM-adipocytes suggests that the strategies targeting FAO warrant further exploration in elderly AML (acute myeloid leukemia) patients.Reference
Fatty acid oxidation and the heart
As already mentioned, blocking FAO is highly effective against heart damage and heart related conditions, such as angina.
Pharmacological suppression of cardiac fatty acid oxidation with reciprocal activation of carbohydrate oxidation, has been successfully applied to the treatment of angina pectoris.Reference
Again, as mentioned before, optimal glucose oxidation is necessary for effective contraction.
Moreover, inhibition of fatty acid oxidation and stimulation of glucose oxidation increases cardiac efficiency in the failing heart as has been demonstrated in a variety of animal models.Reference
Meldonium, which inhibits carnitine synthesis, thus limiting FAO, is also highly beneficial for the heart.
The putative effects that have been ascribed to meldonium in animal studies include prevention of atherosclerosis progression, reduction of infarct size following myocardial ischaemia, attenuation of ventricular remodelling, protection against left ventricular dysfunction, improvement of functional heart parameters, and decrease of both incidence and severity of cardiac arrhythmias.Reference
And finally in a human study, meldonium improves heart function.
After 10–14 days of therapy, patients receiving meldonium (1000mg/day) displayed major clinical improvements and more favorable changes in cardiac structural and functional parameters than those receiving only standard therapy.Reference
Fatty acid oxidation and insulin resistance
Excess fatty acid oxidation inhibits proper glucose oxidation. Inhibiting fatty acid oxidation, in this case with malonyl-CoA, improves insulin sensitivity.
Metabolomic studies have found that mice fed a HFD (high fat diet) demonstrate incomplete oxidation of fatty acids, which is also accompanied by an increase in whole body fatty acid oxidation . This, in turn, contributes to insulin resistance in skeletal muscle. In this model, inhibition of malonyl CoA decarboxylase (MCD) increases glucose oxidation. Ussher et al.  studied the effects of diet-induced obesity in wild-type mice and mice deficient for MCD (-/-) on insulin-sensitive cardiac glucose oxidation. MCD deletion was found to increase cardiac insulin sensitivity in HFD mice; diet-induced obesity is associated with reduced insulin-stimulated glucose oxidation compared to low fat-fed WT mice. Moreover, MCD (-/-) mice subjected to diet-induced obesity display increased insulin-stimulated glucose oxidation and less incomplete fatty acid oxidation. This is associated with a decrease in long-chain acylcarnitines compared with wild-type mice.Reference
One of the concerns is that, what happens with the fat if it’s not oxidized? I’ll elaborate more on that in just a bit, but in animal studies where they inhibit FAO with very large doses of FAO inhibitors or completely deleting the enzyme CPT1, then fat does accumulate in the muscles and liver. However, this does not promote insulin resistance or inflammation, as you’ll see in the next section.
Inhibiting fatty acid oxidation improves insulin sensitivity despite an accumulation of fats.Reference
Fatty acid oxidation and inflammation
It’s often thought that the accumulation of saturated fat via diacylglycerol (DAG) or ceramides are toxic to the cells or that polyunsaturated fats promote inflammation due to lipid peroxidation or by being used by the COX and LOX enzymes. However, just the excess presence and beta-oxidation of fats are toxic to the cells and promote inflammation.
Thus, our data suggest that excess fat is sufficient to activate inflammatory signaling pathways in skeletal muscle resulting in elevated chemoattractant chemokines that in turn increase infiltration of pro-inflammatory immune cells in muscle.Reference
The effect above is very similar to the inflammatory effect of endotoxins, probably because endotoxins also promote the excess oxidation of fats.
Deleting the enzyme CPT1 in animals massively drop their beta-oxidation rate, but not completely, because they can still burn short and medium-chain fats. Inhibiting FAO to a large extend is shown to dramatically lower inflammation in animal studies.
Taken together, these data suggest that inflammatory status is improved in skeletal muscle in Cpt1bm−/− mice despite the presence of excess lipids at the systemic and tissue levels. Toll-like receptors (TLRs) are involved in bridging the immune response to metabolic disturbances as a nutrient sensor and as a part of inflammatory signalling29,30,31. Increased amounts of FA directly induce Toll-like receptors (TLRs)25,32. LPS, a metabolic endotoxin is also increased in obese, insulin resistant mice, and exacerbates inflammation via the TLR4-signalling.Reference
Fatty acid oxidation inhibition and metabolic efficiency
Opposed to what low carb “gurus” would have you believe, blocking excess fat oxidation increases metabolic function (R).
You also don’t have to go low carb to activate AMPK, because inhibiting fatty acid oxidation increases both AMPK and mTOR (R).
This leads to better muscle building or at least muscle retention as well as improved mitochondrial biogenesis and increased peroxisomal fat oxidation.
Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity… Food intake was similar between groups, however, the CPT-1 deleted group didn’t gain weight and was protected against fat gain. TNF-α mRNA levels were significantly less in Cpt1bm−/− mice by 16 wk. up-regulation of markers for FAO and uncoupling in adipose tissue. However, our results clearly show substantial increases in both DAGs and ceramides, and yet no detriments to insulin signaling.Reference
Remember that people with energy-deficient/dysfunction conditions have fewer mitochondria than their healthy counterparts? Well, AMPK will help to create more mitochondria. Combine an FAO inhibitor, such as mildronate or Pyrucet with stearic acid (to promote mitochondrial fusion) and you’ll have more, larger and better-working mitochondria in no time.
Also, the increase in peroxisomal beta-oxidation is important to note.
In peroxisomes, long-chain fatty acids are metabolized to medium- and short-chain acylcarnitines for further oxidation in mitochondria, which prevents the mitochondrial accumulation of toxic long-chain intermediates. In this way, FAO inhibitors decrease the risk of a long-chain fatty acid and metabolism mediated mitochondrial injury.
Peroxisomal beta-oxidation generates H2O2 and no NADH and FADH2, so it doesn’t generate ATP similar to mitochondrial beta-oxidation.
The H2O2 is toxic to cancer cells, it also inhibits excess lipolysis, protects against insulin resistance, activates an anti-aging program in the cell and promotes longevity despite increased oxidative damage of macromolecules (R).
Overexpression or enhanced activation of peroxisomal beta-oxidation makes animals resistant to obesity (R). So enhancing peroxisomal beta-oxidation is a valid strategy to speed up metabolic rate and stay lean.
Fatty acid oxidation and fibroblast growth factor 21 (FGF21)
Inhibition of mitochondrial FAO induces FGF21 expression specifically in skeletal muscle (R).
FGF21 increases glucose uptake under low insulin conditions, however, it does not contribute to the resistance to diet-induced obesity (R). FGF21 is anti-inflammatory and speeds up energy expenditure (R).
Fatty acid oxidation and exercise performance
FAO inhibitors, such as mildronate, are often used to enhance sports performance and it’s on the list of prohibited supplements/drugs in sports.
The way it enhances exercise performance is by improving peroxisomal utilization of fatty acids by the exercising muscles, decreasing production of lactate after exercise, improving storage and utilization of glycogen, as well as preventing oxidative stress after intense muscular workload.
These effects predictably translate into enhanced aerobic endurance and physical work potential, improved functional heart activity, ameliorated recovery after maximal and sub-maximal loads of exercise, and enhanced activation of central nervous system functions.Reference
Fatty acid oxidation inhibition as a nootropic
FAO inhibition appears to improve patients’ mood; they become more active, their motor dysfunction decreases, and asthenia, dizziness and nausea become less pronounced.
Supplements that inhibit fatty acid oxidation
Tianeptine can inhibit FAO, but it has a more potent inhibitory effect on short and medium-chain fats and not as much on long-chain fats (R).
Valproic acid (R).
Anti-hypoxia supplements. Hypoxia increase FAO. A few things that can improve tissue oxygenation include vitamin B1, B2, B3, B5 and methylene blue.
Butyrate and niacinamide. HDAC inhibitors such as trichostatin A, butyrate and niacinamide significantly decreased nuclear expression of CPTI (R).
Avocatin B, found in avocado, is an odd-numbered carbon lipid that inhibits FAO (R).
Salicylic acid. It impairs mtFAO via the generation of CoA and/or L-carnitine esters, which decreases the availability of these cofactors for the β-oxidation (R).
H2O2 inhibits lipolysis. Aspirin and peroxisomal beta-oxidation produces H2O2 and keeps a lid on excess lipolysis (R).
Meldonium is one of the most well known FAO inhibitors, by inhibiting carnitine synthesis.
Pyrucet directly inhibits FAO.
Erucic acid (C22ω-9) (R). Stimulation of peroxisomal FAO by erucic acid inhibits mitochondrial beta-oxidation.
Rounding off by addressing a few last concerns
Fatty acid oxidation inhibition and fat loss
So you might be thinking right now: “How on earth do you lose fat if you don’t burn it?”
Like already mentioned, inhibiting mitochondrial beta-oxidation increases peroxisomal beta-oxidation. Peroxisomal oxidation of fatty acids is not linked to ATP formation, and the released energy is converted to heat. Inhibiting fatty acid oxidation also improves energy production and uncoupling (which burns fat), which helps burn off more calories.
Inhibiting fatty acid oxidation increases mitochondrial biogenesis, and then you’ll have more mitochondria that will be able to burn fat. Remember, its the excess (incomplete) fat oxidation that becomes an issue. Increasing total mitochondria and improving their effectiveness will help to burn more calories overall and help with fat loss.
Plus, fatty acid oxidation isn’t blocked 100%. It’s maybe blocked 20-30% by a drug or higher, depending on the dose ofc, but never 100%. If carnitine synthesis is inhibited, mitochondrial beta-oxidation decreases, because there aren’t enough fats entering into the mitochondria. Still, short and medium-chain fats can enter, so there will always be some beta-oxidation going on.
Plus, if there are little carnitine available, then carnitine turnover improves.
The increase in mitochondrial fatty acid oxidation was observed despite low plasma carnitine levels, and was linked to strongly induced gene expression of carnitine acetyltransferase, translocase and carnitine transporter, suggesting an efficient carnitine turnover.Reference
If the mitochondria is 100% unable to burn fat, then peroxisomal beta-oxidation burns off a lot of fat.
Inhibiting fatty acid oxidation doesn’t stop fat loss. You don’t have to maximize fat burning to lose fat. Fat loss isn’t determined by the amount of fat that you burn.
I’ve already written two articles on this topic.
As I mentioned previously, a good fat loss trick would be to block FAO with something like mildronate or Pyrucet for 30-60 days and use 25g of stearic acid with it each morning. This will improve mitochondrial biogenesis and mitochondrial fusion, which will skyrocket energy production and potentially fat loss as well. Combine this with uncouplers, such as calcium, salt, aspirin, methylene blue, progesterone, and then you have an even better combo. As a side note, stearic acid is also a good uncoupler.
You will most likely not experience weight loss when using an FAO inhibitor such as meldonium, but you will also not gain weight (R), however, it can reduce appetite and food intake, which will help with fat loss.
Fatty acid oxidation and fat accumulation in the muscle and liver
There is a concern that, if you block FAO, what happens to the fat? Does it accumulate in the muscle and liver?
There are no human studies according to my knowledge on the day of this writing, that shows that blocking FAO results in fat accumulation in the muscles and liver.
There are some animal studies showing that mildronate increases fat in the liver, whereas others show that it doesn’t (R, R). Only large doses for long-term periods might promote fatty liver. But as already mentioned, this doesn’t promote insulin resistance or inflammation.
Our results provide evidence that long‐term mildronate administration induces significant changes in carnitine homeostasis, but it is not associated with cardiac impairment or disturbances in liver function in rats.Reference
As you can clearly see from the evidence, blocking fatty acid oxidation actually has a lot of benefits and is not nearly as bad as you might have thought.
IMO, it’s essential for restoring health that has been destroyed by chronic stress.
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