Metabolic Flexibility: Clinical Guide for Obesity Management

We’re all probably familiar with the staggering rates of obesity and overweight, but did you also know that a mere 12% of Americans are considered metabolically healthy? That should concern all of us who are working to keep people healthy, whether we focus on obesity or not.

The term “metabolic health” covers a lot of ground, but one area it includes is metabolic flexibility. Metabolic flexibility refers to the body’s ability to switch easily between burning glucose and fatty acids. The body needs this flexibility to maintain energy homeostasis between periods of energy intake and fasting. Historically, when people sometimes had to go for long periods without eating, this ability helped ensure survival.

Some lay publications refer to it as fuel flexibility, and it is tied to trends of intermittent fasting. (However, evidence on the relationship is lacking. More on that later.) Its opposite is metabolic inflexibility or metabolic resistance, which is associated with obesity, insulin resistance, and type 2 diabetes.

What Is Metabolic Flexibility?

As we know, the body first burns circulating blood glucose, followed by stored glycogen, then fat as fuel for mitochondrial processes. The excess caloric intake common in modern society leads to the more continuous availability of blood glucose, apparently eroding the body’s ability to transition among these energy sources.

Excess glucose initially gets stored in the liver or skeletal muscle, then converted to triglycerides and stored in fat cells. This buildup can lead to insulin resistance and, eventually, to type 2 diabetes.

Studies of metabolic flexibility used to focus on how it relates to the use of energy in skeletal muscle. However, we now know that this relationship also matters to the brain, liver, adipose tissue, and other organs. It is driven by cellular and organelle processes, notably in the mitochondria.

Metabolic flexibility is a sign of efficient metabolic function. It means the body can better maintain its energy equilibrium under changing conditions. It is also crucial for exercise, as the body expends fuel in a way that best fits the energy needs of the activity.

Metabolic Flexibility vs. Metabolic Health: What’s the Difference?

Metabolic flexibility is one marker of metabolic health; they are not the same thing.

Metabolic health is generally determined by assessing whether the following factors fall within the normal range without medical intervention:

• Waist circumference
• Fasting glucose and insulin levels
• Blood pressure
• Lipid profile
• Liver enzymes

Metabolic flexibility/inflexibility is harder to measure than these other five factors, but it is a sign of dysregulated metabolic health.

What Are the Benefits of Metabolic Flexibility?

Individuals with greater metabolic flexibility can expect to experience:

• More steady energy levels, as opposed to spikes and crashes
• Greater endurance during exercise
• Improved insulin sensitivity and more efficient processing of glucose by cells
• Increased fatty acid oxidation, or better fat burning, which can lead to weight loss

Many of these benefits enhance an individual’s ability to exercise, which, in turn, contributes to overall better metabolic health and potentially, weight loss.

Conversely, challenges of metabolic inflexibility may include:

• Insulin resistance
• Weight gain
• Incessant hunger or food cravings
• Sluggishness or fatigue

How Do You Measure Metabolic Flexibility?

There is no set method for measuring metabolic flexibility, and so there are no specific diagnostic criteria. Instead, healthcare professionals tend to look at the accepted measures of metabolic health.

With more interest in metabolic flexibility, including on the part of the public, there are several proposed methods for measuring it. It has been suggested that measuring metabolic flexibility during exercise could serve as a method for the early detection of metabolic syndrome. The question becomes, then, how to measure it.

Calorimetry During Exercise

Because metabolic flexibility affects how the body switches between fuel sources during exercise, this presents an opportunity to measure what is happening in the body. Expired gas analysis during exercise is the common method. However, the medical community lacks consensus on guidelines, protocol, or interpretation of the data collected.

Expired gas analysis, or indirect calorimetry, measures oxygen and carbon dioxide captured by a mask or hood. Analyzing the ratio between them, the respiratory exchange ratio (RER) during exercise can provide insight into how efficiently the body is using energy.

• Higher RER value = primarily burning glucose
• Lower RER value = primarily burning fat

Results depend on differences in analysis methods, data averaging, and the type of exercise. Without standardization, it becomes difficult to compare reported results. Furthermore, these tests usually measure respiration for two to 10 minutes, with a maximum of about 20 minutes being practical.

Whole-body Room Calorimetry

While impractical for widespread use, a whole-body room calorimeter is a more comprehensive way to measure respiration. Measurements over a long timeframe provide better insight into the patient’s metabolism.

A room calorimeter lets people stay in a controlled environment for days or hours, allowing them to move around and take part in everyday activities. Meanwhile, researchers can measure energy expenditure in real time and calculate RER.

Blood Biomarkers

Mitochondria provide insights into metabolic (as well as other types of) disease. Work is underway to identify blood-based biomarkers for many pathologies. More specifically, researchers are looking at platelet mitochondrial bioenergetics. Platelet mitochondria play a role in cell metabolism, activation, and regulation of viability. A blood test could theoretically offer a noninvasive surrogate measure of systemic metabolism.

Tissue Biopsies

Another, more invasive measure is to biopsy skeletal muscle and adipose tissue. Samples would be taken after fasting and after eating, then compared in a laboratory setting. Examination can reveal oxidative capacity, lipid accumulation, and other metabolic data.

Other Measures

Other indicators that have been used to assess metabolic flexibility in clinical research include glucose and insulin kinetics, metabolomics, and transcriptomics. Researchers Yu, et. al., write, “Omics studies have identified potential novel indicators of metabolic flexibility, which provide greater granularity to prior evidence from canonical approaches.”

Even without exact measurements of a patient’s metabolic flexibility, you can make inferences about it based on a full understanding of their health and lifestyle, along with other markers of metabolic health.

How Can Patients Improve Metabolic Flexibility?

It is possible for someone to make their metabolism more flexible, improving metabolic and overall health. The steps a patient should take to improve metabolic flexibility are simply the steps anyone should take for a healthy metabolism. Key lifestyle factors like a balanced diet, regular exercise, and adequate sleep all play a role in how the body uses energy.

Dietary Approaches

Patients should strive to keep their blood sugar as stable as possible by reducing their intake of refined or processed carbohydrates and empty calories. Instead, they should focus on consuming healthy fats, protein, and fiber. They can monitor their blood glucose to help keep it in range and to better understand how different foods affect it. Wearing a continuous glucose monitor (CGM) has become popular among people without diabetes as a way to calibrate their diet.

With a strong public interest in keto diets, many people also monitor their ketones. The body produces ketones when it switches from burning glucose to burning fat for energy. It is relatively easy for an individual to measure their ketones at home with a breath meter or urine strips.

Intermittent fasting is often recommended in the lay literature as a way to improve metabolic flexibility. Although it has been shown to reduce body weight and improve metabolic markers, its relationship with metabolic flexibility may be more complicated.

A 2024 mouse study showed that, in healthy mice, intermittent fasting improved metabolic flexibility. However, in mice with obesity or diabetes, it did not improve it and may even have had a deleterious effect.

Exercise & Physical Activity

As mentioned earlier, metabolic flexibility can increase endurance during exercise. The reverse is also true. Endurance exercise increases the capacity of mitochondria to meet energy demands. A study showed that exercising in a fasted state increases this effect, essentially training the body to shift between burning glucose and burning fat while preserving some glycogen stores.

It is also well documented that building muscle improves metabolism, since muscle burns more calories than fat, even in a resting state. So, strength training in addition to cardiovascular exercise could help an individual improve their metabolic flexibility.

Medications

Weight loss medications, including the newer class known as GLP-1 receptor agonists, can positively affect metabolism. Studies are now looking at dual- and triple-receptor agonists, which target glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG) pathways in addition to GLP-1. Studies suggest that GIP receptor agonists allow the body to switch more effectively between burning glucose and fat — in other words, they improve metabolic flexibility.

Bariatric Surgery

Bariatric surgery can be a highly effective weight loss treatment for the right candidate. Beyond weight loss, the procedure can also improve insulin resistance and metabolic function. The results may owe themselves to the altered physiology of adipose tissue and the function of adipocytes themselves. Bariatric surgery improves insulin sensitivity and shifts the distribution of fat from visceral to the subcutaneous compartment, an arrangement that is correlated with overall metabolic health.

FAQs

Can improving metabolic flexibility help with weight loss?

Because metabolic flexibility enables the body to use energy more efficiently, it may lead to less fat storage and greater burning of existing fat stores. This means it does facilitate weight loss.

Is metabolic inflexibility reversible?

Metabolic flexibility or inflexibility is not a permanent state. Metabolism changes with alterations to exercise, nutrition, and sleep, along with factors like age, hormones, and general health.

What role do mitochondria play in metabolic flexibility?

Mitochondria determine how cells use energy. They are responsible for switching energy sources, a hallmark of metabolic flexibility. Diet and exercise affect mitochondrial function, improving or harming their ability to maintain energy homeostasis.

Does fasting improve metabolic flexibility?

Intermittent fasting can improve overall metabolic health and lead to weight loss. However, its specific role in metabolic flexibility is still unclear and may depend on whether the person already has diabetes or obesity.