As you might have heard, nearly all of the AHS 2013 videos are unwatchable due to technical and production failures. Therefore, I’m publishing my own presentation here in written form, exactly as it was given at the 2013 Ancestral Health Symposium in Atlanta—including slides.

This work is likely to be controversial, as it directly contradicts a great deal of received wisdom—both within mainstream obesity research and within the ancestral health community. The evidence places the energy requirements of the individual cell, and defects of energy production at the cellular level, at the beginning of the causal chain of both obesity and the metabolic syndrome.

However, as my bibliography shows, both metabolic flexibility and its origin in mitochondrial energy production are well-established, easily measurable phenomena—particularly within the field of exercise physiology—and the body of research continues to accumulate, finding defects of cellular energy production within the pathology of numerous diseases, from Alzheimer’s to Type II diabetes. It’s an exciting field—and it gives us both a theoretical framework in which to understand real-world phenomena, and many useful takeways for everyday life.

Yes, these pathologies are multifactorial. And, as I said in my 2012 AHS presentation on hunger, I don’t claim to have made a revolutionary new discovery. I’m bringing an existing field of research to light, and integrating it into our understanding.

So: here it is. Put on your thinking cap and enjoy.

Introduction

Hello. I’m J. Stanton, gnolls.org.

You may wish to open the bibliography in another browser tab or window so that you can follow the references.

Life requires energy.

The human body contains somewhere between 10 and 100 trillion individual cells. Each one of these trillions of cells must continually convert fuel into energy in order to keep itself alive—and, thereby, keep us alive. In fact, a substantial fraction of our body mass is dedicated to providing a constant supply of fuel to every one of our trillions of cells, and removing the waste products of their energy production. Our respiratory system; our digestive system; our circulatory and lymphatic systems; substantial parts of our endocrine and nervous systems; and, lest we forget, each of these systems is itself made up of cells with their own energy requirements.

In short, the reason that large animals, including humans, are so heinously complicated is because every one of our 50-plus trillion cells requires a massive, complex, interdependent infrastructure to ensure it receives both an uninterrupted supply of fuel and of the cofactors required to burn it—independent of wild variances in energy demand via activity level and external temperature, and wild variances in energy supply via meal timing and composition.

Therefore, when we’re asking high-level questions such as “What causes obesity and the metabolic syndrome? And why did that process accelerate so dramatically after 1979?” it behooves us to examine our internal infrastructure—our energy supply chain—for bottlenecks and disruptions.

(Please note: While I’m happy to throw around terms like homeostasis and oxidative phosphorylation, I will use layman’s terms when possible in order to make this talk more accessible.)

What Is Metabolic Flexibility?

Unlike an automobile engine, which usually requires one very specific type and composition of fuel, most of the cells in our body can burn several very different fuels. However, we produce the overwhelming majority of our energy from two of them: glucose, the sugar from which starch is also formed, and fat. Metabolic flexibility is the ability to switch back and forth between the two major energy substrates—glucose and fat—based on availability and need.

How Is Metabolic Flexibility Measured?

Without a steady supply of oxygen, our cells can only produce a small amount of energy; they can only produce it from glucose; and the waste products quickly build up within the cell and prevent further energy production. This is called anaerobic respiration: it’s why we can’t sprint or hold our breath for very long, and why lack of oxygen, via blood loss, heart failure, or stroke, kills us so quickly.

In contrast, our cells require oxygen to efficiently extract all the energy from glucose. Furthermore, they require oxygen to burn fat at all! So except for a few specialized tissues, like red blood cells, and a few temporary conditions, like heavy sprinting and holding our breath, almost all of our energy comes from burning fuel with oxygen—called aerobic respiration.

Now. It turns out that a molecule of glucose contains six oxygen atoms—whereas a fat molecule contains only one, and releases a far greater amount of energy to the cell when we burn it. So while fat contains more energy by weight, it takes more oxygen to extract that energy from fat than it does from carbohydrate.

Next: Oxygen enters our body as oxygen gas (O2), but once it’s been used to burn fuel, it leaves as CO2—carbon dioxide. So we can hook a person up to a respirator, and compare how much oxygen and carbon dioxide they inhale with how much they exhale. This process is called “indirect calorimetry”, and it produces two things. First, we get an approximation of how much energy a person is consuming. Second, it produces what is called the Respiratory Exchange Ratio, also called the Respiratory Quotient— an approximation of how much glucose vs. how much fat your body is burning for energy. The RER, or RQ, varies between 0.7, representing 100% fat oxidation, and 1.0, representing 100% glucose oxidation…so lower values mean we’re burning more fat, and higher values mean we’re burning more glucose.

It’s important to note that the RER, or RQ, is a somewhat blunt instrument: it doesn’t account for protein oxidation, gluconeogenesis, or anaerobic respiration, and rapid changes can throw it off. However, it’s a good approximation that is relatively easy and non-invasive to measure.

Why Is Metabolic Flexibility Important?

Both the availability of energy, and our usage of it, change dramatically over time. We can be sleeping or sprinting; cold or hot; eating or fasting; consuming meat, fish, vegetables, potatoes, popcorn, or a Big Gulp. Our ability to adapt to these conditions depends greatly on the ability of our individual cells to be metabolically flexible—particularly our muscle cells, which use the majority of energy from our bodies. For instance:

• When we ingest carbohydrate, metabolic flexibility helps us control blood glucose, by burning glucose instead of fat. Our RER should be high.
• When we ingest fat without carbohydrate, met flex helps us burn the fat instead of storing it. Our RER should be low.
• When we fast (and everyone “fasts” while they sleep), met flex helps us burn the fat stored on our butt, instead of becoming hungry for sugar or going catabolic. Our RER should be low.
• When we exercise, met flex lets us burn more stored fat and produce more energy at all levels of effort. We can run faster, jump higher, move more weight, and go longer on less food before we “hit the wall.”

What Happens When Metabolic Flexibility Is Impaired?

When met flex is impaired, our cells can’t easily switch fuel sources: the RER, or RQ, is stuck in the middle. This leaves us unable to respond well to changing conditions. For instance:

• When we ingest carbohydrate, we cannot dispose of blood glucose as quickly as we should. This causes poor glycemic control—wide blood sugar swings.

• Our ability to burn fat in response to high-fat meals is reduced.
• Consequently, we have a decreased ability to increase energy output after meals (called “post-prandial thermogenesis”.)

• When we fast, our ability to burn our own fat is diminished.
• Since our ability to burn fat is diminished, we have a continual demand for glucose, even at rest. Therefore, fasting makes us hungry more quickly—and becomes catabolic more quickly.
• Therefore, a metabolically inflexible person attempting to fast or restrict food intake is very likely to also reduce their metabolic rate.
• When we exercise, our ability to burn our own fat is diminished, and our demand for glucose increases.

What Are The Real-World Consequences Of Impaired Metabolic Flexibility?

Now that we know what’s happening internally, let’s examine what that means. In particular, I ask those with experience losing weight, and in attempting to maintain a weight-reduced state, to listen closely and critically.

• If we have poor glycemic control, that means we have higher and more rapid blood sugar spikes and crashes. We all know this is unhealthy—but it also makes us more dependent on stimulants and bready, sugary snacks to maintain our mood, our attention span, and our ability to stay awake after meals.
• A continual demand for glucose at rest means we will become hungry much sooner after eating. Specifically, we become hungry for sugar and carbohydrate in order to “keep our energy up”
• Then, if we manage to ignore these hunger signals through willpower, our body is likely to reduce our energy expenditure in response, making us feel tired and listless, and making weight loss even more laborious. (At extremes, this can manifest itself as poor cold tolerance, and other signs and symptoms of hypothyroidism.)
• Consequently, intermittent fasting and heavy caloric restriction are likely to be both difficult and unsuccessful for the metabolically inflexible. And I suspect this to be a primary mechanism behind the so-called “low carb flu”.
• Finally, a continual demand for glucose during exercise means we will be dependent on a steady supply of energy drinks, bars, gels, and other sugary treats in order to perform physical activities that usually don’t even burn the energy we’ve ingested.

Do these consequences sound familiar to anyone?

Why Is Metabolic Flexibility Impaired?

To answer this question, we must first ask “Is metabolic flexibility a byproduct of neural and endocrine signaling, or is it an intrinsic property of individual cells?”

It turns out that if we measure the metabolic flexibility of individuals, then remove a sample of their muscle tissue and measure its response to fat and glucose in vitro (i.e. outside its neural and endocrine environment), we find the following:

“The interindividual variability in metabolic phenotypes was preserved in human myotubes separated from their neuroendocrine environment, which supports the hypothesis that metabolic switching is an intrinsic property of skeletal muscle.” (Ukropcova 2005. Also see Corpeleijn 2010, Berggren 2008)

So: while elucidating the precise mechanisms involved is still what’s known as an “active research area,” we can be reasonably sure that we are not just looking at an artifact of a broken hypothalamus or a dysfunctional HPTA axis.

What is this defect? Actually, there are two.

Metabolic inflexibility towards glucose—a low “insulin-stimulated RER”, the inability to increase glucose oxidation—appears to be limited by the glucose disposal rate: cells can’t burn more glucose because they’re insulin resistant. They can’t absorb it quickly enough.

In contrast, metabolic inflexibility towards fat—the inability to increase fat oxidation in response to fasting or fat intake—appears to be caused by mitochondrial dysfunction. (Mitochondria are the tiny organelles within each of our cells that actually perform aerobic respiration, turning fuel and oxygen into energy via the citric acid cycle—also known as the Krebs cycle or the TCA cycle.)

And while I’ll save the citation bombardment for my bibliography, which is available online,
I’ll note that this is both a subject of extensive recent research and a robust experimental result. Sample quote:

“Upon a more thorough analysis of the different components of metabolic flexibility, we found that in vivo mitochondrial function was the single predictor of basal RER.” (van den Weijer 2013)

To summarize the current consensus:

• Impaired glucose oxidation, an inappropriately low RER, is due to insulin resistance.
• Impaired fat oxidation, an inappropriately high RER, is due to mitochondrial dysfunction.
• Both are metabolic defects at the level of the individual cell.

How Does Metabolic Flexibility Become Impaired?

This is a fascinating subject and a continuing area of active research, and I would require another presentation to do it justice—so permit me to summarize the current state of the scientific literature.

First, an important note: obesity and metabolic inflexibility are not equivalent! Significant populations exist of both obese normoglycemics and skinny Type 2 diabetics. That being said, let’s explore some possible causal relationships.

• Higher basal RER is associated with subsequent weight gain, independent of total energy expenditure. (Zurlo 1990)
• Fasting, post-prandial, and exercise-stimulated fat oxidation are impaired in the prediabetic. (Corpeleijn 2010)
• When overfed, healthy first-degree relatives of Type 2 diabetics gain substantially more weight than those without such a family history. (Jenkins 2013)
• Quote: “…An impaired ability to increase fatty acid oxidation precedes the development of insulin resistance in genetically susceptible individuals.” (Heilbronn 2007)
• Quote: “Metabolic inflexibility, lower adaptation to a HFD, and reduced muscle mitochondrial mass cluster together in subjects with a family history of diabetes, supporting the role of an intrinsic metabolic defect of skeletal muscle in the pathogenesis of insulin resistance.” (Ukropcova 2007)

In other words, fat oxidation seems to fail first—and though we don’t yet know how, insulin resistance appears to be among the consequences of it. And in support of the mitochondrial theory:

• Quote: “…Mitochondrial content is lower across the continuum of insulin sensitivity and is not limited to T2DM.” (Chomentowski 2011)
• Mitochondria from obese Type 2 diabetics oxidize fat at a lower rate, even after adjusting for mitochondrial mass.
• Mitochondrial dysfunction is observed in relatives of Type 2 diabetics that are not yet themselves insulin-resistant.

In summary:

• Impaired met flex begins with an inability to increase fat oxidation in response to fasting, diet, or exercise.
• This propensity is strongly heritable, probably due to mitochondrial dysfunction.
• Insulin resistance follows, which causes an inability to increase glucose oxidation in response to diet. We are now metabolically inflexible.
• Impaired metabolic flexibility is not a byproduct of a broken brain, a damaged liver, or a faulty thyroid. It is a pair of metabolic defects at the level of the individual cell, multiplied by the trillions of cells that make up our muscle tissue until the effects become directly and objectively measurable via the respiratory exchange ratio.

How Can We Regain Our Metabolic Flexibility?

First, we must remember that we have multiple problems: metabolic inflexibility towards glucose, which manifests itself as poor glycemic control—and metabolic inflexibility towards fat, which manifests itself as poor response to fasting, calorie restriction, and low-carb diets.

The proven way to improve your insulin sensitivity—and, thereby, your met flex towards glucose—is to decrease your fat mass. However, weight loss alone does not improve fat oxidation! Basal RER remains just as elevated in the post-obese as it does in type 2 diabetics and the pre-obese.

So, we have successfully restated the problem as “To lose fat, first you must lose fat.”

And now it’s time to talk about exercise. We know that exercise temporarily helps dispose of blood glucose even in the insulin resistant, and that insulin sensitivity temporarily increases after exercise. However, what’s far more important is that exercise, unlike weight loss, is proven to restore fat oxidation—both basal RER and in response to a high-fat challenge meal.

“…A defect in the ability to oxidize lipid in skeletal muscle is evident with obesity, which is corrected with exercise training but persists after weight loss.” (Berggren 2008)

So. How much exercise do we need? We don’t know the minimum amount…but 3-5 45-minute sessions of moderately intense aerobic exercise per week, or 3 30-minute moderate aerobic sessions and one session of weight training, have been tested and proven sufficient to restore basal rates of fat oxidation to the level of healthy control subjects. And if you’re willing to do that 30-45 minutes every day, you can do so in about ten days.

Let me be clear. Exercise is not important because it burns calories! Exercise without calorie restriction is a remarkably ineffective weight loss intervention, because it usually makes us hungry enough to replace the calories we burn. Exercise is important because it restores your ability to oxidize fat—both when fasting and after meals. And we can tie this in with mitochondrial dysfunction by noting that exercise is proven to increase mitochondrial volume.

Caveat: your results may vary. Here’s the response of several healthy, lean individuals to a decrease in carbohydrate content of their diet: all over the place. So just because a study says the average obese person restored their metabolic flexibility after ten days of consistent exercise doesn’t mean you will.

Other interventions: We can decrease the carbohydrate content of our diet. For someone in energy balance, over time, basal RER will tend to converge towards the ratio of carbohydrate to fat in the diet. However, contrary to dogma which says “Don’t exercise until you’re fat-adapted,” it might be better to start exercising before playing with macronutrients—so that you have the metabolic flexibility to use them.

Finally, since the metabolically inflexible will tend to go catabolic more quickly, it’s probably a good idea to ensure you’re eating plenty of good-quality protein with each meal. And, while continual snacking is counterproductive, it’s probably not a good idea to try intermittent fasting right away. In fact, tolerance for fasting is a reasonably good diagnostic for impaired fat oxidation: if you feel light-headed after a few hours without food, you may be experiencing metabolic inflexibility regardless of your weight, bodyfat percentage, or BMI.

Conclusions and Summary

• Metabolic flexibility is the ability of our bodies to switch back and forth between their two major energy substrates: glucose and fatty acids.
• Met flex allows us to control blood sugar after eating, burn fat while fasting, and otherwise respond appropriately to changes in energy supply and demand.
• Met flex is typically measured via changes in the Respiratory Exchange Ratio (RER), aka the Respiratory Quotient (RQ), which approximates the ratio of fat to carbohydrate our bodies are burning during the time period measured.

• Metabolic inflexibility begins as a cellular-level impairment of the ability to increase or diminish fat oxidation.
• Impaired fat oxidation contributes to insulin resistance, and a consequent inability to increase or diminish glucose oxidation.
• Current evidence suggests that impaired fat oxidation is mitochondrial in origin, genetically and epigenetically heritable, and is among the causes, rather than the consequences, of obesity and insulin resistance.
• Moderate exercise can restore your ability to oxidize fat. Fat loss can restore your ability to absorb and oxidize glucose.

Takeaways

• You can’t exercise your way out of a bad diet.
• You can’t diet your way out of not exercising.
• Exercise is not important because it burns calories: it’s important because it restores metabolic flexibility.

So:

• Eat plenty of complete protein.
• Play frequently.
• Push your limits occasionally.

And whether we brand it as “Paleo,” “Primal,” “Ancestral Health,” or, as I do, “Eat Like A Predator”—it’s good to know that our recommendations are on a sound footing—evolutionarily, empirically, and biochemically.

I’m J. Stanton, gnolls.org. Thank you.

(My bibliography is available at this link.)

I am confident that this avenue of research will continue to provide both explanations for real-world phenomena, and useful takeaways for everyday living. Much more fascinating data has come to light in the months since this presentation—and though we are in the early stages of integration, I currently believe pathologies as disparate as depression, Parkinson’s, and the metabolic syndrome will be linked via defects of energy production at the level of individual cells. Further, I believe that the resulting neural and hormonal imbalances will frequently be shown as effects, not causes: attempts by the brain (and other regulatory organs) to maintain a broken homeostasis.

Yes, these pathologies are multifactorial…and we’re still trying to figure out exactly how mitochondrial energy production becomes impaired. However, I wish to be clear about which direction the evidence is currently leading me.

Live in freedom, live in beauty.

JS

I’m proud of this one: spread it using the widgets below. Also, this is your last chance to get a “Die Biting The Throat” T-shirt—so jump on over to the pre-order page and pick one up before they go away.