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What Is Hunger, and Why Are We Hungry?
J. Stanton’s AHS 2012 Presentation, Including Slides

The response to the written version of my 2013 AHS presentation has been overwhelmingly positive. Based on page views, the number of people willing to read my work greatly exceeds the number of people willing to watch it in video form!

Therefore, I present to you the full text of my presentation to the 2012 Ancestral Health Symposium—including slides. (The original video can be found here.)

This is some of my finest work. It provides a theoretical and practical framework for understanding hunger—an understanding sadly obscured by oversimplification and moralizing, from both scientists and policymakers. This is doubly unfortunate because the science of hunger is well-established, uncomplicated, and consonant with real-world experience.

I’ll leave you with the “Learning Objectives” from the program:

Upon completion of the session, participants will be able to:

  • Enumerate and understand the mental and physical processes which interact to produce hunger.
  • Describe how evolutionarily discordant diet and behavior can cause inappropriate hunger signals.
  • Address some of their own hunger issues, and/or further investigate the subject in their own research.

Note: You may wish to bring up the bibliography in another browser window in order to follow along with the references.


Hello. I’m J. Stanton, gnolls.org.

People aren’t obese because they enjoy being obese, and diets don’t fail because people dislike being slim and healthy! Diets fail because hunger overrides our other motivations.

There is an inflection point somewhere around 1980. What happened? The standard explanation is that fat people are just gluttonous and lazy, so:

Well…maybe not.

It’s also popular to blame junk food…

So much for that idea.

Lately it’s become popular to blame fast food…

But the data doesn’t support that either. (The blue line is food eaten away from home, the red line is fast food…and we can see that the increase in fast food actually slowed down in the mid-1970s, just before obesity began skyrocketing.)

Note from JS: I have been specifically accused of misrepresenting this data. This is a very serious charge—so let me demonstrate that my interpretation is correct. Let’s compare the time periods from 1962 (the first year for which we have obesity data) to 1979, and from 1980 to 2008 (the last year for which we have obesity data).


  • 0.51% per year increase in fast food, as % of total food dollars
  • 0.09% per year increase in adult obesity
  • 0.03% per year increase in extreme obesity
  • 0.08% per year increase in child obesity
        (Child data begins in 1966, and is adjusted for the shorter timespan.)


  • 0.23% per year increase in fast food as % of total food dollars—less than half the rate during 1962-1979
  • 0.67% per year increase in adult obesity—7.4x the rate during 1962-1979
  • 0.16% per year increase in extreme obesity—5.3x the rate during 1962-1979
  • 0.39% per year increase in child obesity—4.9x the rate during 1962-1979

My interpretation of the data stands.

Why We Can’t Just Blame “Palatability” or “Reward”

Now before I explain the science of hunger, there is a very simple and seductive model which is wrong—and if we fall into it, we’ve made a logical error from which we can never, ever recover. That error is: food has a property called “palatability”, or “reward”, which causes us to eat it. So if a food has too much palatability—it’s “hyperpalatable”—we overeat it and get fat.

First, as we’ve already discussed, this hypothesis doesn’t fit the data.

The second problem is that palatability is like pornography. We all know it when we see it—but we just can’t seem to give it a rigorous definition.

For instance, why do different people like different foods? Hundreds of millions of people around the world find these foods delicious. Why can I get twelve different sauces for my chicken wings? 31 flavors of ice cream? And that is because, just like pornography, palatability is subjective. It is a property we assign to food.

The second problem is: why do we ever stop eating? All Oreos taste exactly the same…yet at some point, we don’t want any more. The Oreo didn’t change: we did.

The third problem is that the foods we overeat often aren’t the foods that taste the best—the classic conundrum being “I like prime rib much more than I like Pringles…but I can’t stop eating the Pringles. Why not?” Low-carbers get this all the time: “Your food isn’t really rewarding…it just tastes like it.”

So: what happens now is that the naive model does a little shuffle step. It redefines palatability as “that which we can’t stop eating”. (Or, it substitutes the generic term “rewarding”.)

In other words, “We overeat that which we overeat…because it’s overeatable.”

Of course, if we’re writing a grant proposal, we’ll use the term “obesogenic”. And with that little shuffle step, we’ve just bypassed the entire science of hunger.

Now. I’m beating this dead horse for a very good reason, which is that like phlogiston, spontaneous generation, and the luminiferous ether, this very simple and very seductive error absolutely prevents us from understanding hunger. Once again:

Palatability and reward are subjective properties we assign to food based on our past experience, and our current nutritional and metabolic state.

What Is Hunger?

So: what is hunger?

It turns out there is a large body of established science. I could easily teach a semester-long class, I asked for forty minutes, and they gave me twenty—so I’ll do my best.

Hunger is not a singular motivation. It is the interaction of four different clinically measurable, provably distinct biochemical processes:

  • Satiety: Our body’s nutritional and metabolic state. It includes both our biochemical response to the absorption of nutrients, and our access to stored nutrients.
  • Satiation: An estimate of future satiety, based on the sensory and cognitive experience of eating.
  • Hedonic impact (“likes”): The pleasure we experience from an action. “Palatability” is the hedonic impact of food.
  • Incentive salience (“wants”): Our actual motivation to obtain something we “like”. It is largely, but not exclusively, a product of the other three motivations.

Two more factors interact with hunger to modulate our food intake:

  • Availability: How difficult it is to get something we want.
  • Willpower: The conscious overriding action of the forebrain, known as “executive function”.

Availability and Willpower

Let’s talk about availability for a moment. Even though we might want prime rib much more than leftovers, we eat the leftovers because they’re what’s available to us. If I want prime rib, that’s three hours and a trip to the store, or 40 dollars and a trip to the restaurant. In contrast, we don’t have to want processed snack foods much at all, because all we have to do is open the bag.

They’re not hyperpalatable — they’re hyperavailable.

The Reward System—Hedonic Impact (“Likes”) and Incentive Salience (“Wants”)

Time doesn’t permit me to explore the biochemistry and neuroscience of the reward system—so for the details, I’ll point you to the pioneering work of Dr. Kent Berridge, whose work I was proud to introduce to the community last July. [In this article series, starting with the very first installment. References are also linked in my bibliography. -JS] A couple quick notes:

It’s important to note that likes and wants are not limited to food. Any experience we “like” — that has hedonic impact—is capable of producing a “want” for more—incentive salience.

It is also very important to note that what is colloquially called “reward” is a mashing together of hedonic impact and incentive salience. Both vary independently, and both are subjective properties—so the term “food reward”, which implies a singular property of the food itself, is intrinsically misleading—because it drops us right back into the cognitive trap of the naive model.

But if liking and wanting are subjective, what determines them? Yes, taste is one part of it, but the interesting question isn’t why we eat: it’s why we can’t stop eating.

And so we move on to satiation and satiety.

Satiation and Satiety

Two quick examples: You’ve just left the all-you-can-eat Brazilian steakhouse. What tastes good to you right now?

Almost nothing.

Now: you’ve just hiked seventeen miles over three mountain passes with a 40-pound pack, and that dehydrated lasagna is the best thing you’ve ever tasted.

Again, the food didn’t change—but somehow its hedonic impact, how much we like it — and, therefore, its incentive salience, how much we want it—did change.

Now. Satiation and satiety are synonyms in common usage: so why do we distinguish them? The answer lies in gastrointestinal transit time: it takes hours for the nutrients in food to be digested and absorbed, which means that the satiety response is not a useful signal to stop eating.

(I deleted this passage from the speech as given, because I was concerned about running out of time. However, I think the concepts are valuable, so I’ll reprint it here.)

Furthermore, we must distinguish two types of satiation: positive and negative. When we eat real food, we are rewarded twice: once by the pleasure of eating, and again by the pleasures of positive satiation and satiety.

In contrast, negative satiation is that sick feeling we get when we’ve eaten too many empty calories. It’s our body’s way of telling us “We can’t dispose of any more of that.” So we receive that quick hit of pleasure, or hedonic impact, from eating tasty but nutritionally empty non-food—but it’s over the moment that candy slides down our throat, and we never receive the hedonic impact of positive satiation and satiety that tells us “You’re done, you can stop eating now.”

And with each bite of empty calories, we not only receive less and less pleasure—we make it more and more difficult to achieve the pleasures of positive satiation and satiety.

Furthermore, because satiation is the sensory experience of eating, it can be fooled. It’s well known that:

  • People eat more in groups than when eating alone
  • People eat more when they’re able to eat more quickly
  • Hidden calorie preloads are never completely compensated for

However, the failure of dietary fiber to affect body weight or fat mass in controlled interventions (Papathanasopoulos 2010) suggests that faking satiation with indigestible bulk is not a useful long-term strategy for weight loss. You can fool satiation, but you can’t fool satiety.


And satiety is the key to understanding hunger, because, as we’ve seen:

  • Satiation is just an estimate of future satiety based on the sensory and cognitive experience of eating.
  • Both our likes and our wants are very strongly modulated by satiation and satiety.

If we do an experiment where we sit teenagers down at the mall food court and let them have all the food they want for an hour, we find that the lean kids eat a huge amount of food—nearly as much as the obese kids. (Ebbeling 2004) In other words, both groups want the same amount of food. The difference is that the lean kids compensate for that over the rest of the day, but the obese kids do not. And this strongly suggests that obesity is primarily a failure of satiety.

So: we are clearly converging on a primarily nutritional model of hunger, because that’s the definition of satiety. Let’s explore some of the evidence.

We can begin by asking the obvious question: “What else could hunger possibly be for?” Any animal whose faulty perceptions and motivations caused it to become obese, emaciated, malnourished, or poisoned by excess would have been strongly selected against.

Moving on to the science: taste receptors are not just located on our tongues—they’re located throughout our bodies. (Steinert 2011, Iwatsuki 2012) In our intestines, they modulate the release of satiety hormones like CCK, NPY, VIP, and GLP-1. In the pancreas, they modulate the release of insulin, among other systems…and these effects are so powerful that:

“…The postabsorptive effects of glucose are sufficient for the postingestive behavioral and dopaminergic reward-related responses that result from sugar consumption.” (Oliveira-Maia 2011)

[In other words, you can inject sugar into a rat and get the "food reward" response...even though the rat never tasted the sugar. Also see de Araujo 2008, Ren 2010, Oliveira-Maia 2012. -JS]

Yes, satiety is rewarding in itself…so by eating food that doesn’t produce satiety, you’re chasing a reward that never comes. Does this sound familiar?

Our taste buds both produce and respond to satiety hormones (Shin 2010)…which directly alter the perception of taste. So it might not be your imagination that food doesn’t taste as good when you’re sated.

There are opioid receptors in the walls of your portal vein (Duraffourd 2012)…and they’re not there because your liver wants to get high. They’re a protein sensor—they bond to freshly digested protein fragments.

So, now that I’ve convinced you a nutrient-driven model of satiety and hunger is both biologically and evolutionarily plausible, let’s review some of the experimental evidence.

  • The obese tend to be deficient in many different micronutrients: iron, calcium, zinc, vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, B1, B2, B12, folate. (Leão 2012, García 2009, Xanthakos 2009, Kaidar-Person 2009)

But that’s associative data, so let’s talk about some interventions:

  • Protein leverage. Animals from rats to people tend to eat until they’ve ingested a sufficient amount of complete protein to meet their daily needs.
  • Women given multivitamins lose weight and fat mass: women given placebo do not. (Li 2010)
  • If calories are held constant, weight and fat remain the same, but the placebo group experiences greater hunger than the multivitamin group. (Major 2008)
  • Calcium and vitamin D supplementation alone can decrease body weight and fat mass, but ONLY if you are calcium-deficient. (Major 2009)

And here’s the blockbuster, courtesy of nutrition pioneers Dr. Donald Davis and Dr. Roger Williams:

Feed rats a plausible human diet. Not the “cafeteria diet”, not a “high-fat” diet, a real food diet. Meat, flour, eggs, vegetables, and fruit, all ground up together so it’s uniform. Split them in two groups, supplement one group with a very comprehensive list of vitamins, minerals, and other micronutrients, and let them feed freely.

Then, after several weeks, give both groups free access to granulated sugar for an entire day.

The non-supplemented rats—eating a plausible whole-foods diet of meat, flour, eggs, vegetables, and fruit—consumed 67% more sugar than the supplemented rats. (Davis 1976)


And this is something we absolutely cannot explain via the palatability model. The sugar didn’t change…the diet didn’t change. The only difference is micronutrient content.

So: satiety modulates reward

…and junk food is self-reinforcing. The more empty calories you eat, the more you’ll crave empty calories.

Why It’s Critically Important To Understand Hunger

The problem with popularizing for mass consumption is that it’s easy to simplify a concept until it’s no longer true. In the process of oversimplification, concepts also become politicized—and the naive model, in which palatability is a property of food that causes obesity, is being used to resurrect the diet-heart hypothesis.

The story goes like this:

You have not become fat, sick, and diabetic because we’ve been telling you to eat the wrong foods for 35 years! These massive surpluses of corn, soy, and wheat we’ve created by an agricultural policy that subsidizes the destructive chemically-based monocropping of genetically modified birdseed by giant multinational corporations are completely a coincidence. And our dietary edicts, from the original Dietary Guidelines for Americans to the Food Pyramid to the Food Plate are not just excuses to turn you into passively compliant grain disposal units—which consequently require heroic doses of highly profitable, patented pharmaceuticals to keep you alive. No, no, no.

That is NOT the problem. Pay no attention to the 500 billion dollar income stream behind the curtain.

You are the problem, because YOU DID IT WRONG.

You didn’t eat those hard, dense, bitter whole grain breads we told you to. You’ve been putting salt and butter on your vegetables. You’ve been putting dressing on your salad. You’ve been eating food that tastes good, not the dry, tasteless, low-fat whole grains we told you to.

But that’s okay. It’s not really your fault. We know you’re weak and stupid and can’t be trusted to make your own decisions. The fault lies with those evil corporations who have been making food that tastes too darn good, and you just can’t resist it. So we’re going to save you.

We’re going to tax sugar! Because just like liquor taxes have stopped us from drinking, sugar taxes will stop us from drinking soda and eating candy.

That is the new narrative. And there are people here playing footsie with it.

And THAT is why we must understand the real science of hunger.

First, because we quite literally can’t afford not to. 35 more years of the obesity epidemic will bankrupt Medicare, our government, our health care system, and us.

But far more important is that the cost in human lives and human suffering will be incalculable. Millions will suffer terribly and die needlessly. Been to a cheap nursing home lately? It’s an ugly reality.

However! There is good news, which is that the real science of hunger is not complicated—and if I’ve done my job here, you now have enough of a handle on the concepts to figure out for yourself how the science of hunger applies to your own research, and your own issues around food. And I challenge each one of you—individually and collectively—to follow the path of science, not the path of politics.

So I’ll close with some takeaways.


  • Hunger does not exist to make us fat. It exists to keep us alive.
  • Hunger is the interaction of four biochemically and neurologically distinct motivations: likes, wants, satiation, and satiety.
  • Our resulting desire to consume is modulated by availability and willpower.
  • Cells and organs throughout our bodies are full of taste and nutrient receptors that sense their external and internal environment. In response, they issue hormonal and neural signals in order to maintain an environment which keeps them alive and functional. These homeostases define our current nutritional and metabolic state—our “satiety”.
  • “Palatability” and “reward” are not properties of food. Our likes and wants are subjective properties we assign to food based on our past experiences, and our current state of satiation and satiety. (Remember the rats.)
  • Our food consumption is primarily determined by its ability to produce satiation and satiety, not its hedonic impact.


  • Obesity is primarily a failure of satiety.
  • Your mother was right. The problem isn’t “hyperpalatability”: it’s empty calories.

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

(My bibliography is available at this link.)

Let me be clear. This is the best theoretical and empirical framework we currently have for understanding hunger. Any concept or phenomenon we’re having difficulty with can be reduced to its effect on the four motivations (likes, wants, satiation, and satiety) and two modifying factors (availability and willpower)…and any hypotheses that conflate, bypass, or oversimplify them (e.g. treating “reward” as a property of food) will inevitably produce contradiction, confusion, and a lack of progress towards our goal of better health.

I invite my readers to analyze their own observations about hunger using this framework!

Live in freedom, live in beauty.


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What Is Metabolic Flexibility, and Why Is It Important? J. Stanton’s AHS 2013 Presentation, Including Slides

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.


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.

Metabolic inflexibility is a metabolic defect 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.

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.


  • 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.


  • 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.


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.

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Intermittent Fasting Matters (Sometimes): There Is No Such Thing As A “Calorie” To Your Body, Part VIII

Caution: contains SCIENCE!

In previous installments, we’ve proven the following:

  • A calorie is not a calorie when you eat it at a different time of day.
  • A calorie is not a calorie when you eat it in a differently processed form.
  • A calorie is not a calorie when you eat it as a wholly different food.
  • A calorie is not a calorie when you eat it as protein, instead of carbohydrate or fat.
  • A calorie is not a calorie when you change the type of fat, or when you substitute it for sugar.
  • A calorie is not a calorie at the low end of the carbohydrate curve (< 10%).
  • Controlled weight-loss studies do not produce results consistent with “calorie math”.
  • Even if all calories were equal (and we’ve proven they’re not), the errors in estimating our true “calorie” intake exceed the changes calculated by the 3500-calorie rule (“calorie math”) by approximately two orders of magnitude.

(This is a multi-part series. Return to Part I, Part II, Part III, Part IV, Part V, Part VI, or Part VII.)

What’s More Important: Losing Weight, or Not Gaining It?

It’s instructive to keep in mind that these two questions are not the same—and as such, they may have different answers:

  • What diet will help me lose weight most easily and efficiently?
  • What diet will stop me from gaining weight most easily and efficiently?

As we saw in Part II, the entire obesity crisis in America resulted from the average American gaining roughly one pound per year. So instead of asking “How can we lose weight?” it’s perhaps more important to ask “How can we avoid gaining weight in the first place?”

The first question is answered by underfeeding studies: the second question is answered by overfeeding studies. I’ll return to this important distinction later in this series.

Intermittent Fasting, Time-Restricted Feeding, and “High-Fat Diets”

Cell Metab. 2012 Jun 6;15(6):848-60. doi: 10.1016/j.cmet.2012.04.019. Epub 2012 May 17.
Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet.
Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S.
(Fulltext here)

Mice under tRF consume equivalent calories from HFD as those with ad lib access, yet are protected against obesity, hyperinsulinemia, hepatic steatosis, inflammation, and have improved motor coordination.”

Experimental setup: Half the mice were fed standard chow, half were fed the standard “high-fat diet”. Each half was subdivided into ad libitum-fed mice, who had 24/7 access to food, and time-restricted mice, who only had access to food for eight hours out of 24.

I use scare quotes around “high-fat diet” for several reasons, many alluded to in the previous installment.

First, the “high-fat diet” contains 20% purified sugars.

Second, unlike the standard chow diet, which contains actual food similar to the natural diet of seed-eating, primarily herbivorous mice (the primary ingredients are “ground corn, dehulled soybean meal, dried beet pulp, fish meal, ground oats”), the “high-fat diet” consists entirely of purified laboratory ingredients (the primary ingredients are “lard, casein, maltodextrin, sucrose, powdered cellulose, soybean oil”), none of which occur in or resemble the natural diet of mice. (PDF of ingredients for chow diet, high-fat diet.)

Result: instead of speaking of a “chow diet” and a “high-fat diet”, it’s more appropriate to speak of a species-appropriate diet, or “natural diet”, and a species-inappropriate diet, or “industrial diet”.

Returning to the study, we have four groups of mice: natural/ad-lib (“NA”), natural/time-restricted (“NT”), industrial/ad-lib (“FA”), industrial/time-restricted (“FT”).

First, we find that despite the radically different diets and restricted feeding windows, all four groups consumed almost exactly the same number of “calories”:

Calories consumed, by group

Interestingly, both time-restricted groups (NT and FT) were more active than the ad-lib groups (NA and FA):

Energy expenditure by group

However, only one of the groups got fat: the group which ate the industrial diet ad libitum.

Body weight, by group

The extra weight was almost entirely fat mass:

Body composition by group

Just to make the point clear, the researchers even included pictures of a representative FA and FT mouse:

FA = ad-lib industrial diet. FT = time-restricted industrial diet

Remember, both mice not only ate the same diet—they consumed the same number of “calories” each day.

How about that?

There is much more fascinating data in this paper: at the risk of overquoting, here are some passages of interest. (Emphasis mine.)

Mice fed normal chow or high fat diet under a tRF regimen (NT and FT) improved diurnal rhythms in their RER compared to their ad lib fed counterparts, with higher RER during feeding and reduced RER during fasting, indicative of increased glycolysis and fat oxidation respectively (Figure 1C).
Despite equivalent energy intake from the same nutrient source, FT mice were protected against excessive body weight gain that afflicted FA mice (Figures 1J, 1K and S1), suggesting that the temporal feeding pattern reprograms the molecular mechanisms of energy metabolism and body weight regulation.
mTOR induces the expression of glucose-6-phosphate dehydrogenase (G6pdx) (Duvel et al., 2010), whose protein product is the rate limiting enzyme of the PPC and is activated by accumulation of its substrate G6-P. In turn, the PPC is a major source of NADPH which reduces glutathione. In the livers of mice under tRF, induced expression of G6pdx along with elevated G6-Pled to increased activity of the PPC as measured by higher levels of PPC intermediates and of reduced glutathione (Figures 3D, 3E and S3).
FT mice were also protected from the hepatomegaly and elevated serum alanine aminotransferase (ALT) levels that are associated with obesity-induced hepatic steatosis (Figures 4J and 4K). […] Livers from the FT mice did not have the profound increase in intracellular fat deposits, reduced mitochondrial density and reduced endoplasmic reticulum that were characteristic of the liver samples from the FA mice (Figures 5C, 5D and Table S2).
The tRF regimen temporally reprograms glucose metabolism away from gluconeogenesis towards glycolysis, reduced glutathione and anabolic pathways. Accordingly, FT mice did not display the hallmarks associated with glucose intolerance found in diet-induced obesity, instead showing glucose tolerance and insulin levels comparable to the control NA mice (Figures 3I and 3J). The overall improvement in metabolic state also paralleled improved motor coordination in the mice under tRF paradigms (Figure 3K).
Elevated β-oxidation and reduced fatty acid synthesis in the liver coupled with increased BAT energy expenditure observed in the FT mice prevented the adipocyte hypertrophy common to BAT and white adipose tissue (WAT) derived from the FA mice (Figures 6F and 6G). Furthermore, inflammation marked by extensive infiltration of macrophages and expression of proinflammatory genes, including TNFα, IL6 and CXCL2 that are generally found in the WAT of the FA mice, were attenuated in the FT mice (Figure 6H). Even in mice fed normal diet, tRF reduced the expression of inflammatory cytokines in the WAT. In summary, the tRF paradigm affected multiple tissues and improved whole body energy homeostasis, and reduced inflammation.

A Bonus Observation

Tucked into the corner of Figure 4, we see a curious graph: the FT mice (industrial “high-fat” diet, time-restricted) performed best of all the groups on the accelerating Rotarod test.


“What’s a Rotarod?” you ask.

(Perhaps the fact that ketones are the preferred fuel of the brain and heart isn’t just a biochemical curiosity.)

Takeaways: Intermittent Fasting

First, it’s clear that a calorie is not a calorie when you’re intermittent fasting.

However, the most interesting part, to me, is the difference between the natural and industrial diet groups. 16/8 intermittent fasting was only mildly beneficial to the mice eating a natural diet. However, the mice fed an industrial diet ad libitum (“FA”) were not only obese—they were in terrible metabolic shape, with fatty liver and impaired glucose metabolism. In contrast, the time-restricted industrial diet mice (“FT”) were, for the most part, just as healthy as the mice fed a natural diet.

Tentative takeaway: The less species-appropriate your diet is, the more difference intermittent fasting makes to your health and bodyweight.

This doesn’t mean you can eat all the junk food you want so long as you fast afterward! For instance, nothing about IF will stop gluten grains from causing intestinal permeability (see Fasano 2011). However, it seems that IF may be able to increase your tolerance for dietary patterns that would otherwise be unhealthy for you, cause weight gain, or both.

Also, I can’t resist the observation that most agrarian religions prescribe a significant amount of fasting. John Durant has speculated that this is a disease-fighting measure, but it may well be a general health measure that helps compensate for the inferior agrarian diet.

This series will continue! Meanwhile, you can go back to Part I, Part II, Part III, Part IV, Part V, Part VI, or Part VII.)

Live in freedom, live in beauty.


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