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Metabolic Flexibility, Intermittent Fasting and the New England Journal of Medicine 

By January 19, 2020 One Comment

So, there’s is A LOT to unpack in this post but I’m going to tackle, yet again, the benefits of intermittent fasting, explain “metabolic flexibility” and share some highlights from an exciting publication from the prestigious New England Journal of Medicine. 

A little background on human energy sources: 

Humans have been around quite a while.  Humans need to eat food for fuel.  Eating provides fuel for the body’s organs to work.  The human brain is relatively small (about 2% of our weight) but also very complex and a bit of an energy pit, using about 20-25% of our energy resources…..which is a ton compared to most other animals, as human beings are capable of doing very complex processes.  We need energy to feed these brains and the rest of our bodies.  

Following so far?  Nothing too complicated yet.   

Most of the scientific community argues that glucose (aka carbs) is the brain’s preferred fuel source.  Whether it’s “preferred” or not, the brain and body will preferentially use glucose over any other energy source (such as fat) when glucose is available.  This is likely an innate survival mechanism as glucose is typically not available in high amounts in nature (unless you come across a honeycomb or something in which about 30% of it is glucose).  Now, our hunter-gatherer ancestors would not have balked at eating carbs if and when they were available, and, in fact, they did eat carbs depending on their climate and other factors.  They ate things such as fruit (which were much smaller, less sweet and packed w/ more nutrients than modern fruit), some tubers (potatoes) and the occasional treat of honey if/when they were lucky enough to find some.  Hunter-gatherers also hunted game (both big and small), fished and ate various species of insects (all depending on their geographical area).   

Now, hunter-gatherer groups were not always successful in the hunt (for those of you who hunt you can sympathize!).  They also weren’t always all that successful at gathering (think droughts, ice/snow, insect infestation, etc), and one thing is for darn sure is that they weren’t pounding hundreds of grams of carbs a day to supply their brain and bodies with sufficient energy to not only stay alive, but thrive and reproduce.  So how did ancient humans stay fueled in the absence of glucose (carbs)? 

FAT.  As in F-A-T. 

Fat?  Yes, fat.  In the absence of carbs (or very little carbs) and when the body’s liver and muscles are mostly depleted of glycogen (the stored form of carbs in our liver and muscles), the body will convert its own bodyfat into energy in the liver by making ketones.  This adaptation was essential to the survival of humans as food, especially energy dense foods, was not always readily available in the pre-agricultural era.  Fast forward to 2020.  In 2020, we (industrialized nations) are constantly in the FED state.  We rarely go very long without eating, except for maybe when we sleep.  Hungry?  Walk to the kitchen and grab some chips.  No food at home?  No problem!  Drive down to the Qwik-e-Mart and grab a snack or go through the drive through of a local fast food joint.  Most Americans are following the Standard American Diet (SAD for short) and eating lots of refined carbs and sugars, unhealthy fats and not enough protein.  Unlike our hunter-gatherer ancestors, we are always eating food sources which are energy dense but nutrient poor! This means the foods of the SAD diet are packed with calories but lacking in nutrition.  This causes blood sugar swings and increases in leptin (the hunger hormone) and leaves us constantly hungry and needing to snack.  Since these cheap, nutrient-poor foods light up the “reward” centers of our brain (once again, we are designed to WANT to consume energy dense foods as a primal survival mechanism from a time period when a plethora and never-ending supply of energy dense foods did not exist, as it does today) we don’t know how to stop eating them!  If you are addicted to this endless cycle of hunger, snack food and processed, nutrient-poor foods, IT’S NOT YOUR FAULT.  Yes, I said it, IT’S NOT YOUR FAULT!  You are designed this way!  These adaptations were designed for survival in ancient times of food scarcity.  But, as you know, food is no longer scarce.  So, how do you break this revolving door of high-carb, poor qualify food, blood sugar swings and non-stop hunger? 

Keep reading and we will get there. 

Metabolic Flexibility 

Metabolic flexibility.  It has a nice little ring to it.  It sounds sorta fancy yet kind of complicated.  What exactly does “metabolic flexibility” mean?   

Metabolic flexibility is the ability for humans to effortlessly go between glucose (carb)-based energy system and fat (ketone) based energy system.  As I alluded to above, most Americans are stuck in the glucose-based energy system.  And if they go too long without more carbs they feel tired, irritable and hungry, also known as HANGRY.  Metabolic flexibility is a sign of metabolic health.  It means you have adapted to utilizing various energy systems depending on what you are doing and what you are eating (or not eating).  It means you are avoiding the constant carb/high glycemic roller coaster that most Americans are stuck on.  It means you are limiting the number of unhealthy carbs in your diet and going longer periods of time without eating, allowing your body to tap into its fat reserves for fuel.  Our bodies, at most, contain about 350-500 grams of glycogen (stored carbs) in the muscles and maybe an additional 100 grams in the liver. That’s a total of about 1400-2000 calories.  Fat, on the other hand, is PLENTIFUL (some of us more than others) where even relatively lean people can have as many as 100,000 stored calories from fat!  Absolutely astonishing!  If you deplete your glycogen (carb) stores then your body will start using fat as fuel! If your glycogen stores are always full, you will NEVER lose body fat!! This is why fairly low-carb eating, fasting and moderate exercise are so darn effective!  Keeping carbs on the low side (in comparison to SAD), going longer periods of time without eating and exercise all works to DEPLETE your glycogen stores and tap into your fat-burning potential! 

How do I become metabolically flexible? 

  • Eating  
  • Exercising  
  • Not eating (keep reading and I’ll explain) 

I will briefly summarize some of the important aspect of developing metabolic flexibility.  If you have been consuming a SAD diet for years, please understand that this transition will take time!  For some it might be a week or two and others it might be three or four weeks.  If you already eat healthy and are lean, you might already be metabolically flexible and not even know it! 

Eating the right foods 

Firstly, eliminate processed foods and refined carbs.  Get rid of the bagels, pastries, breakfast cereals, breads, pastas, fruit juices, soft drinks, candy, energy drinks, syrups and anything with sugar.  These are nutrient void foods that will only make the blood sugar roller coaster keep rolling and keep your glycogen stores full, rendering you unable to burn bodyfat. 

Focus on whole food nutrition.  Basically, eat real food!  Lots of veggies, healthy, responsibly sourced animal products, healthy fats (such as extra virgin olive and avocado based products), some nuts and seeds as well as select fruits and occasional starchy tubers (potatoes, sweet potatoes)  These will be low-glycemic and full of nutrition, keeping you satiated and allowing longer periods of time between meals. 

By eating whole foods you will, by default, be eating less carbs, especially the high-glycemic carbs, so you will be more likely to keep glycogen levels lower (stored carbs in the muscles) giving you a better chance at tapping into bodyfat for fuel.   


Exercising on a regular basis will also help you to tap into your bodyfat stores.  I’m not going into great detail here, but a regular exercise regimen that includes both strength and cardiovascular training is ideal.  In addition, keep busy on your feet and try to hit 10,000 steps a day—there is nothing magical about this number, it just means you’ve been active and on your feet!  Exercise, especially full body strength training, is an AMAZING way to deplete glycogen stores.   

Intermittent fasting (IF) 

Intermittent fasting.  Time restricted eating. 5:2 fasting.  Multi-day fasting fasting.  There are lots and lots of intermittent fasting variations.  There is really no agreed upon definition what actually constitutes IF, but there are a few IF strategies that are generally recognized as safe and effective from various studies as well as many, many anecdotes.  There are some fasting zealots out there who think that a true “intermittent fast” is fasting for 24 hours or longer—there are people out there doing regular 3 day to 7-day (and even more) water only fasts! (NOT recommended unless you are truly fat adapted, used to long fasts and/or without medical supervision!). 

The idea of IF is to go a long period of time without eating.  Long enough, in most cases, to where your body switches from glucose (carb) burning to fat (or ketone) burning (which happens when you deplete your glycogen stores).  This can differ depending on the person, fasting the protocol and various other factors.  What happens when you go without eating for an extended period of time on a regular basis is truly quite remarkable! (I will get into this later).   

My recommendation for IF for the average person is utilizing time-restricted feeding.  Although we personally don’t practice this, 5:2 fasting is another reasonable, sustainable alternative.   

Time-restricted feeding (TRF) is limiting the consumption of any calories (from food or beverage) into what is called a “feeding window”.  This follows, or is followed by (depending on your perspective) a fasting window.   

5:2 fasting is picking 2 days each week in which you “fast” by eating very low calories, somewhere in the neighborhood of 500-700 calories for the entire day.  

What is the correct length to fast/feed on a time-restricted feeding plan? 

Well, it depends.  

There are so many factors that play into this I cannot possible break all of these down in this one discussion.  We are all unique individuals at different stages of life, different ages, different stress levels and different body types.  None of this can be generalized.  In fact, it usually takes some degree of self-experimentation or following along with people who can help sensibly guide you in the process. 

If you are currently on the SAD diet, eating/snacking all the time and not fasting other than when you sleep, then clean your diet up first and foremost.   After you adjust to your new eating plan you can start thinking about incorporating some intermittent fasting into your lifestyle.  My opinion is TRF is the most lifestyle friendly, effective and habit-forming practice of IF for most every day, average Joes and Janes.  I’m not going to give all the tips and secrets away!. (If you want to get started on this process check out the program I created with my business partner through our coaching company, Equip For Health, called “Sustain”, which will walk you through getting started on TRF and healthy living 

Intermittent Fasting is so amazing, in fact, there was a recent publication in the prestigious New England Journal of Medicine discussing this topic in further detail, which I will briefly summarize below.  

For those of you who have been following me for any length of time, it is no secret I am fond of IF and have been preaching (and practicing) its attributes for quite some time now.   I am not alone in my sentiments regarding IF!  Not only are many health zealots and biohackers shouting from the rooftops about the amazing benefits of IF, there are many, many medical doctors and PhD researchers also shouting from the rooftops about the benefits of IF.  Animal and human research has been going on for quite some time now studying the effects of IF.  There are many complex processes that take place in the body during the fasted state.  Some of these are not even completely understood!  What is important, are the benefits from regular periods of intermittent fasting. 

Here are some of the noteworthy highlights from the article about IF: 

  • Encourages metabolic switching (also known as metabolic flexibility) back and forth from glucose to ketones 
  • Elicits “adaptive cellular responses” 
  • “improves glucose regulation 
  • “increases stress resistance” 
  • “suppresses inflammation” 
  • “enhance intrinsic defenses against oxidative and metabolic stress and those that remove or repair damaged molecules” 
  • Fights disease: “obesity, diabetes, cardiovascular disease, cancers, and neurodegenerative brain diseases” 
  • “elicits high orchestrated systemic and cellular responses that carry over into the fed state to bolster mental and physical performance, as well as disease resistance” 
  • “increased expression of antioxidant defenses, DNA repair, protein quality control, mitochondrial biogenesis and autophagy, and down-regulation of inflammation.” 
  • “ameliorate obesity, insulin resistance, dyslipidemia, hypertension, and inflammation” 
  • In certain cancers in animal models fasting, “reduces the occurrence of spontaneous tumors” 
  • “alternate-day fasting can delay the onset and progression of the disease process in animal models of Alzheimer’s disease and Parkinson’s disease” 

The article goes into great detail about the physiological effects of IF and notes various other potential benefits along with some other discussions.  Here’s the link to the NEJM article in case you want to read it yourself: 

Thanks for reading! 



Rafael de Cabo, Ph.D., and Mark P. Mattson, Ph.D., N Engl J Med 2019; 381:2541-2551
DOI: 10.1056/NEJMra1905136 


Author Ryan Parnham

Hello and thanks for visiting my site. My name is Ryan Parnham and I'm a 37 year old husband and father of two from central Illinois (hope I haven't bored you yet). The reason I started this site is because I have a passion and desire to live the BEST life possible, and I want to share my thoughts and experiences with other people so they can educate themselves and change things in their lives to live the best life possible as well. I strongly believe that nutrition is one of, if not the biggest, factor in health, vitality and longevity. I feel I have a bit of a unique perspective on things given my professional and personal back ground. I have an undergraduate degree in nursing as well as a master's of science degree in nursing and am a board certified family nurse practitioner from the American Academy of Nurse Practitioners (AANP). I have been in the medical field for over 15 years now

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