How to improve metabolic flexibility to lose fat

I’m not talking about keto or fasting or anything like that.

Metabolic flexibility (MF) is the ability of the body to switch from one fuel source to the other without any problem.

When carbs are eating, insulin shuts down the mobilization of fats (lipolysis) from the fat stores, promotes glucose uptake (GLUT4), storage (as glycogen) and oxidation (pyruvate dehydrogenase (PDH)) and inhibits further fat oxidation (by increasing malonyl-CoA, which inhibit CTP-1).

When glucose runs low again, or when glycogen stores are full and no more glucose are readily available for oxidation, insulin levels drop, malonyl-CoA drop and lipolysis and fat oxidation resumes.

Being insulin sensitive and having the ability to switch between carbs and fats for fuel is being metabolically flexible. Burning just fat as a fuel source results in an RQ of 0.7 and when someone burns just glucose, they have an RQ of 1.

When someone isn’t metabolically flexible, like a diabetic, they are not able to switch from one to the other. At rest, they oxidize both glucose and fats at the same time and when a meal is eaten, glucose oxidation only increases a little and fat oxidation is not shut down. For prevention/treatment purposes, it might be short-sighted to define diabetes or metabolic inflexibility (MIF) as a defect of carbohydrate metabolism alone.

People who are metabolically inflexible have:

  • Inadequate suppression of lipolysis and elevated fat oxidation postprandial (after a meal).
  • At rest there is a reduced rate of fat oxidation and after a meal reduced rate of glucose oxidation (R), meaning neither glucose nor fat is getting optimally oxidized.
  • Excess lipolysis compared to rate of oxidation, which leads to an increase in fat storage in the muscle as diglycerides (DAG) and triglycerides (TAG). Furthermore, the rate of fatty acid uptake in muscle is similar between lean and obese subjects, however, fat oxidation is less for obese subjects, which means that the net storage of intramuscular fat (IMCL) is greater compared to their normal-weight counterparts. Intramuscular fat promotes insulin resistance and dysfunctional cells.
  • Lower activity through the Kreb cycle and electron transport chain (ETC) in the mitochondria. This means less energy production for one.
  • Increased membrane fluidity of the cells, which leads to an increased electron leak, reactive oxygen specie (ROS) production, less insulin sensitivity and reduced ATP production.
  • Longer phosphocreatine (PCr) recovery half-time – about 45% longer than that of healthy people (R).
  • Reduced mitochondrial content; smaller and fewer mitochondria (quality and quantity).
  • Faulty ETC, especially complex I and III. With respect to ETC activity in the subsarcolemmal mitochondrial fraction, there was an approximately 7-fold reduction in type 2 diabetes and a 3- to 4-fold reduction in obesity compared with lean subjects.
  • Incomplete beta-oxidation and fat oxidation, leading to build-up of fatty intermediates and inflammatory fat adducts such as 4-hydroxynonenal.
  • Elevated glucose and glycogen breakdown through glycolysis, but creates lactate instead of entering the Kreb cycle.


How to improve metabolic flexibility

1) Inhibit excess lipolysis

The bigger fat cells get, the more fat it releases through lipolysis. Those fat cells also become insensitive to the anti-lipolytic effect of insulin. Diabetic and obese people have elevated baseline lipolysis compared to lean individuals. Those fats then flood the body and because it can’t be oxidized quickly enough, deposits elsewhere, such as in the muscles and organs.

A good place to start would be to inhibit the excess lipolysis so that the body can first and foremost improve insulin sensitivity (elevate free fatty acids in the blood causes insulin resistance) and get rid of the fat that’s deposited in and around the organs and muscles.

Supplements such as:

are such useful compounds and will inhibit excess lipolysis and improve insulin sensitivity.

2) Decrease fat oxidation and increase glucose oxidation

In MIF, the ability to switch from fat to glucose oxidation is hampered. Inhibiting fat oxidation and increasing glucose oxidation can fix this.

Glycolysis, which is the breakdown of glucose to pyruvate is mostly increased in people with MIF. The pyruvate can then be shuttled into the mitochondria by pyruvate dehydrogenase (PDH) for oxidation or be converted to lactate.

PDH determines MF (R), and it’s mostly decreased with MIF. Increasing it will lower lactate production and increase glucose oxidation and normal oxidative phosphorylation.

Supplements such as:

  • Berberine (R) – (Amazon)(iHerb)
  • Vitamin B1 (Methionine and vitamin E co-administered with thiamine potentiates the boost in PDH) (R) – (Amazon)(iHerb)
  • Palmitic acid
  • Fructose

increases PDH and will promote normal glucose oxidation.

Not a lot of substances can effectively decrease fat oxidation, but saturated fat, which increases malonyl-CoA through lipogenesis have a greater inhibitory effect on CPT-1 (Carnitine palmitoyltransferase I) than unsaturated fat, so should inhibit fat oxidation to a greater extent than unsaturated fat, thus allowing for greater glucose oxidation.

Other than saturated fat, only one product that I know of is able to simultaneously inhibit fat oxidation and stimulate glucose oxidation, which is Pyrucet (from IdealabsDC). It’s a product with two natural ingredients that potently promote glucose oxidation.

3) Improve thyroid function

The active thyroid hormone, T3, increases PGC-1α (which increases mitochondrial biogenesis and proper fuel oxidation) by as much as 13-fold after 6 hours (R). Thyroid hormones also increase AMPK, reduce malonyl-CoA (which inhibit fat oxidation), increases CPT-1 (which transports fats into the mitochondria for oxidation), increase GLUT4 (which transports glucose into cells), TCA cycle activity, UCP (promotes thermogenesis), futile ATP cycling (channels and pumps), etc.

Thyroid hormones and catecholamines, such as noradrenaline (NA), works synergistically together, and NA stimulates the enzyme deiodinase, which converts T4 into T3, thus have a pro-thyroid effect.

However, although noradrenaline can induce browning of the adipose tissue, adrenergic therapy does not activate brown adipose tissue to the same extent as cold exposure, and incurs adverse cardiovascular effects.

Also, the thermogenic response to cold exposure is blunted in people with a sluggish thyroid. So instead of trying to boost catecholamines, first increase thyroid hormones.

4) Use Red light

Phototherapy, such as with red light, promotes metabolic flexibility, reduces fat mass and insulin resistance and promotes muscle mass gains (R). Red light promotes the activity of the ETC by displacing nitric oxide from the enzyme cytochrome C oxidase.

Red light is used for a huge array of conditions, such as chronic inflammation, arthritis, edema, low energy, hypertension, cancers, etc. It even enhances mental function and can have a relaxing effect.

It can be shone on the upper body, neck, face, legs, joints and even the testicles (it actually increases testosterone levels). Even 5 minutes on the upper body should have a good effect and 30 minutes daily should be the goal.

600-800nm would be perfect at close distance.

  • Red light device – (Amazon)


5) Lower nitric oxide levels

Nitric oxide (NO) is mostly known for its vasodilatory effect. However NO boosters usually increase NO by 3-4 fold through the eNOS enzyme, however, other NO boosting enzymes such as iNOS can increase NO by a 1000 fold. That high concentrations are highly detrimental if elevated chronically.

The NO will bind to enzymes in the TCA cycle and to the cytochrome C oxidase enzyme in the ETC. This inhibits the enzymes activity and reduces ATP production and other biological processes.

Red light and methylene blue are able to displace that NO from the enzymes so that normal energy production can occur.

Methylene blue also acts an alternative electron donor, which means that if one of the enzymes of the ETC isn’t working optimally, methylene blue can act as a substitute for that broken enzyme and promote normal energy production.

Methylene blue also promotes mitochondrial biogenesis, so that it not only works as a crutch for broken cells, but also creates new cells that’s not broken.

6) Go low fat diet

Because MIF is the inability to switch between fuel sources, it would be a good idea to eliminate one fuel source, and as your health improves over time, add more of the fuel source that has been eliminated.

I lean towards going low fat because on a low carb diet, the body has to upregulate cortisol to break down protein to make glucose and this also inhibits thyroid hormone production. A high carb low fat diet will have a much greater anti-stress effect.

Additionally, research have found that MIF subjects gained ∼200g more fat than MF subjects after 1 wk of a high-fat diet (2500 calories, 20% protein, 20% carbs and 60% fat) (R).

A high fat diet has also been found to lower the activity of ANT, a transporter that shuttles ADP into the mitochondria to be used for ATP production. This leads to reduced ATP production and increases free radical (H2O2) production. This increases fatty acid and cardiolipin oxidation, DNA and cell damage and cell death.

Limiting fat to about 10-15% is a good start and those fat should come from saturated fat sources, such as butter, cream, beef-, lamb-, venison-, buffalo fat, lean fish, coconut oil, cocoa butter and MCT oil.

Saturated fat rich in stearic acid improves cellular function and stability, promotes mitochondrial fusion, reduces membrane fluidity, electron leak, insulin resistance, which all lead to more ATP production, less oxidative stress, greater state 3 (ATP producing state) and 4 (uncoupling) respiration and bigger and better functioning mitochondria (R).

7) Exercise

The use of exercise is two fold. It promotes fuel partitioning and insulin sensitivity and also promotes mitochondrial function and thus rate of fuel oxidation.

Firstly, exercise promotes insulin sensitivity.

Exercise after meals, compared to exercise before meals, reduces postprandial glycemia and lipemia most effectively in individuals with type 2 diabetes. Walking for even 10 minutes after a meal will help with the digestion and lowering of glucose.

Also, exercise in the evening, compared to exercise in the morning, has a more beneficial impact on glycemia and lipemia. Possibly because we get more insulin resistant later in the day.

However, it’s also good to exercise, like riding a bike or sprinting outside, in the morning in the sun to help with resetting the circadian rhythm and improving glucose tolerance and MF. Most peoples’ circadian rhythm is off because of out of wack eating routines, blue light at night, elevated cortisol, stress, etc. Exercising in the morning in the morning light will help to restore the circadian rhythm.

Alternatively to exercising or walking after a meal, you can also exercise intensely before a meal. This is called “exercise snacking”. It requires that you exercise vigorously for less than 5min before consuming a meal. This way the nutrients from the meal help to replenish glycogen stores and help with cellular repair instead of being stored in the adipose tissue.

Secondly, exercise can be used for creating new mitochondria as well as enhance the quality of the already existing mitochondria. HIIT and weight lifting have the greatest effect on removing damaged or old cells as well as creating brand new 100% functional and metabolically flexible mitochondria.

Moderate intensity cardio is less effective than HIIT at recycling and creating new cells and low intensity cardio is the least effective.

8) Improve your Circadian rhythm

We as humans are supposed to go through light and dark, active and inactive cycles. During the light and active phases we eat and use fuel and during the dark and inactive phases we sleep and the body is able to repair itself.

Giving the body inadequate time for recovery will lead to MIF. Moreover, too long light cycles can lead to obesity by
decreasing brown adipose tissue (less thermogenesis and energy expenditure) activity via impaired adrenergic signalling (R).

A few ways to promote proper circadian rhythm again is to:

  • Get sunlight on you eyeballs each morning. This helps lower melatonin and set the circadian rhythm. Doing this for a while will reduce morning fatigue and make you tired earlier to go to bed for better sleep.
  • Block blue light at night. Blue light lowers melatonin which is a hormone that helps you fall asleep at night. Blocking the blue light will help melatonin to stay high for when you’re ready to go to bed. (Amazon)
  • Go for a walk or exercise in the morning light.
  • Wake up every day at the same time, including weekends.
  • Always go to bed at the same time.
  • Do early time restricted fasting.
  • Eat a big breakfast. Food and light work synergistically together for setting the circadian rhythm.

9) Early time restricted feeding a.k.a. Intermittent fasting, but in reverse

Eating all the time, especially in a big surplus, leads to mitochondrial metabolic “indecision” and ineffective substrate switching, resulting in incomplete substrate utilization for energy production and subsequent storage of substrates in (ectopic) depots (around organs and in muscles) (R).

Cells exposed to a nutrient overload have a fragmented mitochondrial network (smaller in size), whereas upon calorie restriction, mitochondria appear more interconnected (). Increasing mitochondrial elongation and interconnectivity induces a bioenergetic adaptation that increases ATP synthesis capacity and efficiency (). Conversely, fragmentation of the mitochondrial network reduces bioenergetic efficiency and might protect against detrimental effects of nutrient overload.

The body is made to go through feeding and fasting cycles. Feeding in the day, fasting at night. This gives cells the opportunity to recover again.

The problem is most people don’t give their cells long enough to recover. They eat right before bed, sleep for about 7 hours and then eat when they wake up again. On top of that some are also insulin resistant and have elevated blood sugar and insulin during the night which blunts all the repair processes and hormones, such as growth hormones, SIRT, etc.

eTRF is like intermittent fasting, but where the 8 hour feeding window is in the morning instead of the afternoon. With this approach you will skip dinner and this will allow proper preparation for all the repair that’s needed to occur at night. There are many other benefits to this approach, such as fat loss, improved insulin sensitivity and circadian rhythm and so much more. I’ll be writing a more detailed article about it soon.

10) Sleep

Sleep is one of the most important things to do for recovery and promoting MF.

Sleep increases the NAD:NADH ratio, promotes SIRT activity, spikes growth hormone, etc., all which is essential for becoming MF (R).

A few supplements to aid in sleep is:

As always, thanks so much for reading my article.
If you found it helpful and insightful please like and share so others can also benefit from this information and feel free to leave a comment down below if you have any questions for me.

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