Metabolic Inflexibility Drives Increased Appetite
IRP Research Could Aid Personalized Weight Loss Recommendations
A new IRP study suggests that people whose bodies have trouble shifting from using carbs as fuel to burning fats might have larger appetites, putting them at greater risk for unhealthy amounts of weight gain over time.
We all know the stereotype of the picky child who shuns vegetables unless they’re smothered in ranch dressing or cheese. Surprisingly, the human body can also be similarly choosy about how it fuels itself. New IRP research shows that people whose bodies prefer to raid their sugar depots rather than use stored fat during a period without food consume more calories after their fast, suggesting a possible explanation for why some people are more prone to gaining weight over time or have less success with certain weight loss interventions.1
Our bodies are constantly turning the carbohydrates, fats, and — to a much lesser extent — protein that we eat, and that the body stores in times of plenty, into fuel for our cells. The specific mix of those nutrients that the body uses is influenced by a variety of factors, including what we eat. After all, if you eat only plain bread, your body will of course burn more carbs than if you put butter on that bread. Interestingly, though, some people are more capable than others of switching fuel sources under different conditions, a characteristic researchers call ‘metabolic flexibility.’
“Diet is the major driver of the fuel a person’s body uses, but there is a large inter-individual variability,” explains IRP staff scientist Paolo Piaggi, Ph.D., co-first author of the new IRP study. “If you take two people and give them the exact same diet with the exact same calories, they will show a different flexibility to this diet. There are people who naturally burn more carbs and people who burn more fats independent of the diet that is given.”
The energy that powers our cells comes from only three types of nutrients, so when the body resists using one form of fuel, it must use more of another.
Individual differences in metabolic flexibility aren’t just an interesting biological quirk, though. Dr. Piaggi and his colleagues in NIH’s Obesity & Diabetes Clinical Research Section have shown that people who are less able to shift towards burning fats over carbs are more likely to gain weight over time.2 Naturally, after linking lower metabolic flexibility to weight gain, the next step was to figure out the reason for that relationship.
In the new IRP study, Dr. Piaggi and his colleagues recruited 44 healthy participants and confined each of them to a special room called a respiratory chamber for two 24-hour periods. The respiratory chamber allows scientists to measure how much oxygen people breath in and how much carbon dioxide they exhale, which can be used to determine the ratio of carbs and fats that the participants’ bodies are using. During one of the 24-hour periods, the participants were fed a balanced diet with plenty of carbs and fats that matched the calories needed to maintain their weight. During the second period, participants endured an all-day fast designed to reveal how capable their bodies were of shifting away from burning carbs and towards using stored fat for fuel.
Dr. Paolo Piaggi
“It's like a metabolic stress test,” Dr. Piaggi says. “We can really see if a person’s metabolism is flexible under this extreme condition of extended fasting. It’s just like if you have two people and you need to figure out who can move faster. You’re going to ask both of them to run as fast as they can so you can figure out who's better at running, rather than looking at them when they stand or when they walk.”
The researchers found that during the fasting period, on average, the participants’ bodies shifted towards burning more fats and fewer carbs, but there were major individual differences in that transition. The study’s key finding, though, came from examining how much the participants ate when given free access to food the day after fasting in the respiratory chamber. People who were less metabolically flexible — that is, those who shifted less towards burning fat over carbs while fasting — consumed significantly more calories after their fast ended. This provides a potential explanation for why people who are less metabolically flexible might be more likely to gain weight over time.
“If you don't rely much on carbs, then you rely on fats, of course, because these two are the main fuel sources the body uses to make energy,” Dr. Piaggi says. “If you rely a lot on carbs, the body's preferred and most efficient fuel source, then you're going to probably be more prone to overeat when you are allowed to eat, possibly in order to replenish the body's limited carb stores. And if you are more prone to overeat, by extrapolation, you are more prone to gain weight.”
Ultimately, Dr. Piaggi hopes doctors will one day be able to personalize diet recommendations based on a patient’s metabolic flexibility. For patients with obesity, for instance, doctors might use that information to prescribe different types of diets containing different proportions of carbs and fats in order to help their patients lose weight.
The new study’s findings pose the possibility that people who are less metabolically flexible might find it easier to lose weight if they eat plenty of healthy carbohydrate-rich foods like whole grains, fruits, and vegetables, rather than removing carbs from their diet.
Of course, it’s not practical to stick every patient concerned about their weight in a respiratory chamber, so Dr. Piaggi and his colleagues are now looking into whether they can identify certain genes or substances in the blood that influence how metabolically flexible someone is. If they can manage that, not only would doctors be able to personalize lifestyle advice for their patients based on a simple blood test, but scientists could also develop treatments that increase metabolic flexibility to aid weight loss.
“In the future, when we discover the mechanisms underlying metabolic flexibility — whether hormonal or genetic — we can develop drugs or pharmaceutical agents that can compensate for any metabolic defect that predisposes an individual to weight gain and are specific for each person,” Dr. Piaggi says. “This is an example of precision nutrition — precision medicine applied to obesity and weight gain.”
“We think our research is groundbreaking in the sense that we can kind of provide hope to everyone,” he continues. “We need to give comfort to people who, despite cutting their calories, are not losing weight. It's not their fault — it’s just because their metabolic inflexibility reduces the effectiveness of their low-calorie diet. And we need to understand their metabolic flexibility to figure out what’s the specific tailored diet for each person based on their fuel preference in order to get the best outcome.”
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References:
[1] Unlu Y, Piaggi P, Stinson EJ, Cabeza De Baca T, Rodzevik TL, Walter M, Krakoff J, Chang DC. Impaired metabolic flexibility to fasting is associated with increased ad libitum energy intake in healthy adults. Obesity (Silver Spring). 2024 May;32(5):949-958. doi: 10.1002/oby.24011.
[2] Begaye B, Vinales KL, Hollstein T, Ando T, Walter M, Bogardus C, Krakoff J, Piaggi P. Impaired Metabolic Flexibility to High-Fat Overfeeding Predicts Future Weight Gain in Healthy Adults. Diabetes. 2020 Feb;69(2):181-192. doi: 10.2337/db19-0719. Epub 2019 Nov 11. Erratum in: Diabetes. 2021 Apr;70(4):1019.
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This page was last updated on Tuesday, July 9, 2024