Human physiology has evolved during dramatic fluctuations in energy supply and demand. Coping with these challenges has enabled the human body to manage energy metabolism for optimal substrate storage and utilization during either food surplus or shortage and of either rest or increased calorie burn. This ability to efficiently adjust metabolism to fluctuations in energy demand by rapidly and efficiently switching between oxidations of different energy substrates, namely fat and carbohydrates, depending on their availability, is known as metabolic flexibility. More specifically, metabolic flexibility is our body’s ability to switch from high levels of fat oxidation during fasted states to increased carbohydrate utilization during feeding states. The greater our ability to burn the food we consume instead of storing it, the more metabolically flexible we are.
Humans constantly cycle from fasting to postprandial (post-meal) conditions and vice versa. The primary purpose of this substrate shift is to move from catabolic (the metabolic process of breaking down fuels for energy production) to anabolic (the metabolic process of synthesizing molecules such as glycogen and triglycerides for energy storage) activities in which energy can be effectively stored in skeletal muscle, fat, and liver tissues.
Metabolic flexibility is not an ‘’on-off’’ phenomenon. It involves constant, tightly regulated adaptive responses of human metabolism to maintain energy homeostasis by matching fuel availability and demand to various conditions such as periodic fasting, varying meal composition, physical activity, and environmental fluctuations. However, nowadays, when the food supply overflows and there is a plethora of calorically dense processed foods combined with low levels of physical activity, metabolic flexibility is directly obstructed.
In this article, we will review the principle mechanisms that control metabolic flexibility, its implications for health, and the prominent role diet and exercise play in maintaining it.
Physiologic mechanisms leading to metabolic inflexibility
Healthy cells of metabolically active organs such as the liver, skeletal muscle, and fat tissue are metabolically flexible and communicate to organize the utilization of available fuels best. The inability to adapt to fuel availability may result in an abnormal mobilization and utilization of fat and glucose, leading to increased fatty acids and glucose concentration. After fat cells reach a threshold of calorie and lipid capacity, lipids also start to accumulate in other locations other than fat tissue, including skeletal muscle and the liver. This process, known as ectopic fat deposition, leads to lipotoxicity and eventually metabolic abnormalities and disrupted metabolic flexibility. Therefore, the previously healthy cells have now turned into dysfunctional cells.
Metabolic inflexibility is characterized by reduced skeletal muscle glucose transport, increased suppression of fat tissue lipolysis, reduced suppression of hepatic glucose production, and skeletal muscle mitochondrial dysfunction. All these defects result in increased glucose production by the liver, reduced glucose utilization for energy by the muscles, and decreased fat burn. At the core of these processes lies long-term caloric excess and ectopic fat accumulation. As a result, metabolic inflexibility and ectopic fat accumulation reinforce each other in a vicious cycle, causing and further cultivating metabolic dysfunction.
Metabolic flexibility and its association with insulin resistance
Impaired metabolic flexibility is associated with an increased risk of obesity and obesity-related pathologies, such as metabolic syndrome, type 2 diabetes, systemic inflammation, cardiovascular disease, and cancer. Simultaneously, obesity, especially central obesity, where fat accumulates around the abdomen, is the leading cause of insulin resistance. Insulin resistance is the inability of muscle, liver, and fat cells to respond to insulin, thus taking up and utilizing ingested carbohydrates for energy.
Insulin resistance is a vital component of the metabolically inflexible state, which is typically characterized by decreased fat oxidation during fasting and a reduced ability to upregulate carbohydrate oxidation during feeding. Therefore, the ingested carbohydrates are stored as fat in the fat tissues and other organs (ectopic fat).
Insulin resistance is also the predominant factor leading to type 2 diabetes and the link among a constellation of cardiometabolic risk factors known as metabolic syndrome, linking obesity, type 2 diabetes, and cardiovascular disease. Consequently, it’s becoming clear that not only Impaired metabolic flexibility is associated with an increased risk of insulin resistance but that insulin resistance itself deteriorates metabolic flexibility as well; hence why most individuals with obesity and/or type 2 diabetes are metabolically inflexible.
Metabolic syndrome is defined as having at least three components: visceral obesity in terms of elevated waist circumference, insulin resistance in terms of elevated fasting glucose, high blood pressure, elevated triglycerides, and/or low HDL-cholesterol. One of the hallmarks of metabolic syndrome is chronic systemic inflammation. Along with obesity and insulin resistance, systemic inflammation can trigger and propagate metabolic inflexibility. Thus, metabolic inflexibility, inflammation, obesity, and insulin resistance are part of a vicious cycle where the one trigger and reinforces the other. While impaired metabolic flexibility is strongly associated with insulin resistance, which of the two precedes is still unresolved.
Overall, metabolic health is defined as a comprehensive state of well-being, and metabolic flexibility is essential for metabolic health and the absence of metabolic diseases, such as metabolic syndrome.
Mitochondrial dysfunction: The cause or the consequence of metabolic inflexibility?
Mitochondria are dynamic intracellular organelles that play a foundational role in energy metabolism. When energy supply exceeds energy demand across the mitochondria (chronic caloric surplus), their oxidative capacity is reduced, predisposing to adverse health outcomes, such as the development of type 2 diabetes and obesity.
The concept of metabolic flexibility has particularly been associated with the mitochondria’s function and places mitochondrial function at its core. Mitochondria are crucial in determining whole-body metabolic flexibility, and the deregulation of mitochondrial function underlies the onset of metabolic inflexibility. More specifically, mitochondrial dysfunction, in terms of low skeletal muscle mitochondrial capacity, function, and/or density, is associated with reduced resting lipid oxidation and therefore increased muscle lipid accumulation (ectopic fat) and insulin resistance.
Although the hypothesis that such mitochondrial abnormalities may be a primary cause of metabolic inflexibility has been raised, definite conclusions regarding the causal relationship cannot be drawn based on current evidence. However, there is a substantial body of evidence to support the presence of impaired mitochondrial adaptation as a principal component of systemic metabolic inflexibility, particularly in conditions related to insulin resistance, such as metabolic syndrome. Therefore, the relationship between insulin resistance and altered mitochondrial function seems to be bidirectional and mutually amplifying. 
Metabolic flexibility and its relation to physical activity and diet
Several studies have highlighted the positive relationship between sedentary behaviors, such as time spent sitting, and the risk of developing obesity, type 2 diabetes, and cardiovascular disease. Indeed, regular physical exercise is a key determinant of metabolic flexibility, favoring metabolic and cardiovascular health while preventing weight gain and its related metabolic abnormalities. Particularly, exercise training increases metabolic flexibility by reducing insulin resistance and increasing muscle lipid oxidation.
Therefore, it’s becoming clear that exercise profoundly affects metabolic flexibility. This effect is also mediated by the impact of exercise on the mitochondria. Current evidence shows that exercise-trained skeletal muscles, especially endurance athletes, present increased skeletal muscle mitochondrial biogenesis and have higher mitochondrial content, capacity, and function. In other words, exercise-enhanced mitochondrial performance is related to better metabolic flexibility. In contrast, skeletal muscle from individuals with obesity and insulin resistance is metabolically inflexible compared with skeletal muscle from healthy individuals.
Besides physical activity, a chronic caloric surplus is another major factor impairing mitochondrial function and inducing metabolic flexibility. Therefore, weight loss through a suitably-applied caloric deficit is crucial in restoring metabolic flexibility and is the most common intervention for obesity and obesity-related metabolic comorbidities.
Taken together, physical activity, especially aerobic exercise, is an effective way to improve metabolic flexibility. Combined with a proper nutrition regime that will not be characterized by overconsumption of calories and nutrients from highly-processed caloric-dense foods that promote weight gain, thus dysregulation of metabolic health, it can comprise the best strategy to restore metabolic flexibility.
Can breath analysis be utilized as an index of metabolic flexibility?
Metabolic flexibility as individuals alternate between feeding and fasting can be assessed through changes in the respiratory exchange ratio (RER), calculated from the VCO2-to-VO2 ratio measured by breath analysis (AKA indirect calorimetry). RER is an index of the proportion of carbohydrates and fat being oxidized for energy.
In humans, RER typically fluctuates between 0.7 and 1.0, depending on the fuel being oxidized. When fat or glucose is the unique energy source, the RER is 0.7 or 1.00, respectively. In fasted conditions, typically, RER is about 0.80 in subjects fed with mixed diets, while values lower than 0.75 are observed in individuals fed with low-carbohydrate diets (<30% of energy from carbohydrates). Individuals with negative energy balance or fed high-fat diets (>50% of energy from fat) tend to have even lower fasting RER values. However, in a state of increased visceral fat (central obesity) and insulin resistance, there is a higher preference for glucose relative to fat as an energy source in the fasting state (high fasting RER).
The extent to which RER increases from fasting to feeding conditions has been considered an index of metabolic flexibility. An impaired drop in RER during an overnight fast (high fasting RER→glucose oxidation predominance and inability to switch to fat oxidation), as well as an impaired rise in RER in response to feeding (baseline RER of ≈0.85, which fails to increase further), indicates a metabolically inflexible state. Several studies suggest this is the case for obese insulin-resistant and type 2 diabetic subjects.
However, indirect calorimetry should be used with caution and critical thinking to measure metabolic flexibility. Someone should always consider a subject’s energy balance and dietary macronutrient composition while interpreting the results since those factors affect the RER.
In summary, metabolic flexibility is not only a valid term regarding metabolic health. Still, it may actually underlie the epidemic changes in metabolic disease that affect all demographic groups and burden healthcare systems. It may also be an early condition that, if timely detected and appropriately handled, could prevent the onset of several serious metabolic disturbances, such as type 2 diabetes and cardiovascular disease.
Metabolic Health