Metabolic flexibility: Is this the fountain of youth?

Metabolic flexibility is key in helping you avoid many severe health issues – (it’s surprisingly straightforward to achieve) – and it may even drastically slow down the ageing process

Many patients visit the Vitality clinic with vague symptoms such as fatigue, food cravings, brain fog, mood swings, irritability, constant hunger and weight gain. And the influx of these patients has dramatically increased during the Covid-19 pandemic. These symptoms are signs of metabolic inflexibility in people stuck in a sugar-burning mood. We can usually help them to resolve their symptoms with simple lifestyle modifications.

This article covers metabolic flexibility, what makes you inflexible, how to reclaim your flexibility, and how metabolic flexibility benefits health, slows ageing, and prevents disease.

What is metabolic flexibility?

Your body can burn carbohydrates and fat as fuel for energy. Metabolic flexibility means you can switch between them with ease. For example, you can switch from sugar to fat oxidation during an overnight fast or from fat to sugar burning after a meal. The switch in fuel depends on the type and quantity of nutrients available for oxidation.

Using multiple fuel sources gives you good, steady energy levels all day and keeps you at ideal body weight. It also positively impacts your health, preventing disease and slowing down the ageing process.

The concept of metabolic flexibility is linked to the capacity of the mitochondria to select fuel in response to nutritional changes. At a molecular level, metabolic flexibility relies on metabolic pathways that manage nutrient sensing, uptake, transport, storage and utilisation.

Metabolic flexibility is an adaptive response that helps the body maintain energy homeostasis in the face of various factors such as periodic fasting, differing meal composition, and physical activity. This can happen in times of calorie excess or restriction and low or high energy demand, such as during exercise.

The liver, adipose tissue, and muscle are the biggest players in running your metabolism. They communicate via hormones and interact closely with the mitochondria (energy plants) to meet varying energy requirements.

Because adipose tissue is the predominant source of free fatty acids, the capacity of this tissue to store fatty acids during caloric availability, and release fatty acids during caloric restriction, is an important determinant of metabolic flexibility.

Historically, our ancestors used to store excess energy as fat during seasons of abundance (feast) to use during the times of scarcity (famine.)

Are you metabolically flexible?

Do you have stable blood sugar? People with diabetes struggle to control their blood sugar. They often develop severe symptoms at extremely high or low blood sugar levels, during sepsis or after taking too much insulin. More commonly, normal (non-diabetic) people experience blood sugar fluctuations during the day, particularly after meals. They often feel exhausted and want to sleep after lunch (the afternoon energy dip.)

Do you have excellent satiety between meals? Your appetite is normal if you can remain satisfied for five hours after eating without needing your next meal or a snack. But, you have lost control if you have to start carrying food around with you in case you get hungry. I have met many people with the wrong belief that they should not allow themselves to get hungry. This is in addition to the western diet of high sugar and refined carbs, making us constantly hungry. Training your body to use stored fat will stabilise your blood sugar and prevent the hungry (angry) mood.

Can you extend your overnight fast and eat your first meal mid-morning? This is a good way of training your body to burn stored fat since you are moving into a healthy eating pattern known as intermittent fasting. Having your first meal of the day at 10:00 and your last meal at 18:00 gives you 18 hours of fasting and an eight-hour eating window, stimulating your flexible metabolism.

Would you be able to exercise in a fasted state for two hours? In other words, are you a fat burner? Sugar is stored in your liver and muscles as glycogen. If you are a sugar burner, your glycogen will run out, and you won’t be able to continue exercising beyond two hours. Having a flexible metabolism allows you to start burning fat early, leaving some glycogen (sugar) to support the demands of high-intensity activity.

Metabolic flexibility is measured as the change in respiratory quotient (RQ) from the fasted state to the insulin-stimulated state. Measurement is performed using a hyperinsulinemia-euglycemic clamp and hood calorimetry.

How do I become metabolically flexible?

You can adopt a healthy ketogenic diet of low carbohydrate and high fat to prompt your body to burn fat and produce ketones. This will set your metabolism to burn fat (both dietary and stored) for energy. In the transition from your present diet, you may develop ketone flu symptoms of headache, fatigue, body aches and pains, irritability, diarrhoea, or constipation. These recede over time.

Alternatively, you can cycle carbohydrates to gain metabolic flexibility. This means aiming for a low carbohydrate diet but eating an extra serving of carbs once or twice a week to make the change gradually and retain the ability to digest carbohydrates.

Intermittent fasting will allow you to burn enough fat to satisfy your energy needs but release the quantity of toxins (toxins are always stored in fat) that your body can handle.

“They can’t burn a gram of fat, despite their huge store”

Metabolic inflexibility occurs when a person gets stuck in sugar burning mood. They cannot burn a gram of fat, although they have a huge store of it. Metabolic inflexibility progresses to insulin resistance, obesity and metabolic syndrome. It can result in type 2 diabetes, dementia, cancer or even sepsis. Metabolic inflexibility can be improved through healthy lifestyle choices, such as intermittent fasting, a healthy ketogenic diet and exercise.

Research reports that the skeletal muscle of lean individuals shows a remarkable ability to increased fatty acid oxidation after fasting or reduced fatty acid oxidation after insulin infusions, therefore designated as “metabolically flexible.” Insulin-resistant obese patients could not adapt their fuel preference to fasting and insulin, since they manifested a lesser reliance on fatty acid oxidation compared with lean individuals. Because of their inadequate responses to metabolic challenges, these patients were named “metabolically inflexible.”

More recent studies showed that, upon consumption of a high-fat diet, lean subjects with adequate metabolic flexibility were able to increase fatty acid oxidation at the expense of glucose, whereas obese individuals were not. Lean individuals also showed an increased expression of genes involved in fatty acid transport and oxidation compared with little or no change in their obese counterparts.

Your fuel options: glucose, fat, protein

After a carbohydrate-rich meal, the pancreas responds to the rise in glucose by releasing insulin into the bloodstream. Under the influence of insulin, the liver is triggered to absorb glucose from the circulation and stop glycogenolysis (the breaking down of glycogen into glucose) and gluconeogenesis (making glucose from other sources.) Skeletal muscle assists in glucose clearance as the insulin receptor, binding insulin, allowing glucose to enter the muscles.

Adipose tissue responds to insulin by decreasing the rate of lipolysis (the breaking down of fat) and stimulating fatty acid and triglyceride synthesis from lipids and glucose. Collectively, this buffering capacity ensures that the exposure of tissues to high blood sugar is minimised and that energy is stored in adipose (fat) tissue to be used in times of scarcity. Insulin also inhibits lipolysis (breakdown of fat) in the adipose (fat) tissues.

To use fat as fuel, you have to lower your insulin (the fat-storage hormone) and convert fatty acid into ketone bodies. This takes place in the liver, triggered by low insulin (and blood glucose) levels. Ketone bodies replace glucose as fuel: there are three types, namely beta-hydroxybutyrate (BHB) – the most abundant ketone body – acetoacetate and acetone – the least abundant type. These represent an alternative fuel to use at times when glucose supplies are low, such as when going on a ketogenic diet, during fasting and on prolonged exercise. Exercising in the morning on an empty stomach is a good way to generate ketone bodies. Fat is a cleaner fuel compared with glucose, as it produces fewer oxidants and hence causes less muscle soreness after exercise.

BHB is converted into acetoacetic acid to produce the Acetyl COA molecule that enters the citric acid cycle to produce energy. BHB improves brain function and was found helpful in migraine, epilepsy, Alzheimer’s and Parkinson’s disease.

MCH oil, especially C8 (caprylic acid) derived from coconut, can readily convert into ketone bodies. It can be used as an exogenous ketone to fuel exercise. Recently, ketone bodies have emerged as an alternative substrate to improve exercise performance.

Ketone salts (supplement) are ketones attached to salts, typically sodium, potassium, calcium or magnesium, usually provided as a powder that you can mix in a liquid.

The body breaks down protein during prolonged fasting – in particular, muscle protein, i.e. branched-chain amino acids (BCAAs.) The enzyme that activates the breakdown of amino acids becomes inhibited by sufficient levels of acetyl COA and NADH. This ensures that, in underfed conditions and during short intervals of fasting or light exercise, skeletal muscles are preserved.

Your body sets up growth and repair cycles through signaling. For example, mTOR senses the availability of nutrients (during feast time) to stimulate cellular growth, while Beta-Hydroxybutyrate (the most available ketones) triggers autophagy (cellular repair) during times of scarcity. Your body senses your cellular energy status by AMPK signals, boosting or slowing down energy production accordingly.

Exercise: the most effective way to improve metabolic flexibility

Exercise-induced weight loss has a positive impact on metabolic flexibility. Exercise improves metabolic flexibility in its fight against obesity, type 2 diabetes, and ageing. It also prompts your body to burn fat. If you already exercise, you can improve its efficacy by varying your workout.

During moderate and vigorous exercise, 95% of the energy goes to the skeletal muscles. This comes from intramuscular stored glycogen and fatty acids, together with blood glucose and fatty acids. Exercise requires great metabolic flexibility in view of its huge energy requirements.

High-intensity exercise relies on glucose oxidation in the mitochondria, but to a greater extent, on anaerobic glycolysis in the cytoplasm. This occurs independently from insulin, as the levels of insulin are pretty low during high-intensity exercise. Dependence on fatty acid oxidation decreases as the intensity of the exercise increases. The longer the exercise duration, the greater the contribution of fatty acids to the overall energy supply.

Despite having low fatty acid oxidation during a resting state and low-grade exercise, obese people and diabetics may lose weight due to increased fatty acid oxidation during exercise. They also burn more glucose during exercise. This explains the glucose-lowering effect of exercise in the obese and diabetic.

Exercise increases your capacity for fatty acid oxidation at rest and during exercise. This helps you to enjoy sustained higher energy levels all day and to maintain your ideal body weight. Exercise enhances insulin sensitivity with the overall benefit of preventing diabetes, cerebrovascular disease, dementia, cancer and more. The improvement in insulin sensitivity and metabolic flexibility is attributable to increased mitochondrial biogenesis – an increase in their number, content and function.

Research has confirmed that habitual physical activity is a strong determinant of your metabolism. A high level of physical activity makes you metabolically flexible, while physical inactivity and sedentary behaviour trigger a state of metabolic inflexibility, even among individuals who meet physical activity recommendations.

The study observed the subjects as they transitioned from metabolically flexible to an inflexible state during seven days of bed rest. This confirmed the overall negative effect of physical inactivity. Breaking up sedentary time with bouts of physical activity is a stimulus found to improve metabolic health (flexibility) and has been suggested as a promising strategy for the general population.

Insulin resistance is the main cause of obesity, type 2 diabetes and cardiovascular disease

Eating after fasting shifts your body from fatty acid oxidation to glucose oxidation in skeletal muscles. The fuel shift moves metabolism from a catabolic to an anabolic state to store energy in muscle, adipose tissue and the liver. Insulin is released in response to a meal and is the major driver of the metabolic shift. Insulin resistance is the predominant factor in obesity, type 2 diabetes and cardiovascular disease. Impaired mitochondrial fatty acid oxidation in the liver and skeletal muscles is the underlying cause of insulin resistance. This results in the accumulation of excess fatty metabolites such as diacylglycerol.

Reduction in the amount of glucose entering skeletal muscles and adipose tissue from the blood stream, plus the reduced suppression of liver glucose production, results in the elevation of the blood glucose level. In the absence of increased insulin release from the pancreas, diabetes develops due to the failure of the pancreas to compensate with increasing insulin release.

Calorie restriction improves insulin sensitivity but does not seems to enhance the skeletal muscles’ fat acid oxidation to help weight loss. Insulin sensitiser drugs like Metformin can do the same but at the cost of significant side effects.

Age makes people susceptible to many diseases, including dementia, cataracts, diabetes, hypertension, arthritis and cancer. Dietary modulation such as fasting, calorie restriction and ketogenic diet can help to increase the most abundant ketone (beta-hydroxybutyrate.) This can improve your condition and help to prevent various age-associated diseases.

How can I improve my metabolic flexibility?

You can improve your metabolic flexibility by cleaning up your diet, eliminating sugar and refined carbohydrates, alcohol; adding more healthy fats such as avocado, olive and coconut oil, and nuts and seeds. Take dark leafy greens (spinach and kale), more sulfur-containing vegetables such as broccoli, brussels sprouts, cabbage, and asparagus, and low fructose fruits such as berries.

You can eat pasture-raised organic eggs, grass-fed butter, or pescatarian options of wild-caught Alaskan salmon, sardines or herrings. You can continue a steady level of clean carbohydrates, adding an additional serving of sweet potatoes once or twice weekly (cyclical carbs.) Women can increase their carbohydrate intake around their periods or ovulation, as these have a helpful soothing effect.

Try to increase your physical activity across the day. Think about getting a standing work desk. Have adequate periods of proper exercise. Gentle exercise on an empty stomach in the morning may speed up your progress. To reap the most benefit, you should also vary your exercise, to “surprise” your muscles with new movements and thereby generate a deeper response.

Combining a diet plan with intermittent fasting or water fast, exercise, restful sleep, and lower stress will build up sustained metabolic flexibility.

So, my friends, I hope you recognise the role of metabolic flexibility in determining your state of health, your likelihood of contracting various serious diseases, and even the rate at which you age! Despite the severity and complexity of these issues, they can be greatly enhanced by a better diet, enhanced activity, and achieving a state of metabolic flexibility through them and some form of fasting.

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References

Metabolic flexibility as an adaptation to energy resources and requirements in health and disease

https://academic.oup.com/edrv/article/39/4/489/4982126

Metabolic flexibility and insulin resistance

https://journals.physiology.org/doi/full/10.1152/ajpendo.90558.2008#:~:text= nce

Metabolic flexibility in health and disease

https://www.cell.com/cell-metabolism/comments/S1550-4131(17)30220-6

Beta hydroxybutyrate and its metabolic effect on age-associated pathology

https://www.nature.com/articles/s12276-020-0415-z

Sedentary behaviour is a key determinant of metabolic inflexibility

https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP273282#:~: endations

5 signs that you are metabolically flexible