The Metabolic Holy Grail Pt. 1

Adam Plotkin
8 min readFeb 4, 2021


Metabolic Flexibility: The Making of a Fat Burning Body [Video]. (n.d.). YouTube.

Like a phoenix rising from the ashes, I have returned!

For the last 6 months or so I have preparing endlessly for the MCAT, and now that my relentless pursuit towards that stupid test is over and done with, we can get back to the real fun. I’ve got a good, quick article for you all today. Enjoy!

Riddle me this…what’s better: keto, carnivore, vegan, south beach, zone, paleo, high-carb, low-carb, etc… I am sure you can find positives and negatives for each, and of course the literature is conflicted on the efficacy of each in terms of weight loss, body composition, safety, and long-term consequences to name a few. So that begs me to ask the $1,000,000 question: “What is the optimal human diet?”

Well boy oh boy, that is one loaded question. In fact, that is the wrong question to be asking at this point in time. I mean, how do you even define “optimal nutrition?” Well for starters, we can look at some cultures that have seemed to do things right. I am talking about the Blue Zones. If you are new to the nutrition space, you may have never heard of “Blue Zones.” Blue Zones are regions of the world where a higher than usual number of people live much longer than average (1). For instance, the Inuits, Kitavins, Sardinians, and Okinawans are some of my favorite examples, and I will show you why. Let’s look at a macronutrient breakdown of these 4 cultures

Picture extracted from “Plotkin, A. Molecular and Clinical Nutrition Section, NIDDK Scientific Meeting. “Metabolic Flexibility: Using Indirect Calorimetry to Find the Holy Grail.” February 2021

So the Kitavins and Okinawans eat a large amount of carbohydrates, the Inuits eat a large amount of fat, and the Sardinians eat a mixed amount of fat and carbs. The real important common ground is that all 4 cultures eat WHOLE FOODS!!! And despite each culture eating different macronutrients, we see that all 4 of these cultures live longer than average and are predominately free of modern degenerative disease which plagues Westernized civilizations (6). So this makes you wonder…maybe it isn’t the carbs or fats that are driving all the metabolic problems we are seeing in the 21st century. So then what is?

In case you have been living under a rock for the last few decades, let me update you on some major health news: WE ARE IN THE MIDST OF A WORLDWIDE OBESITY EPIDEMIC. According to the CDC the age adjusted rate of obesity in America is roughly 42% (7). No bueno :(

Now, there are one million and one theories as to what causes obesity, and I am not even going to touch those for the sake of this article. But at its core, obesity can simplistically be thought of as a consequence of an altered energy balance in which energy intake chronically exceeds energy expenditure. So let’s look at America’s macronutrient breakdown to compare it to those 4 Blue Zones:

Although this is a dated citation, the current USDA guidelines just give ranges (Protein between 10–35%, Carbs between 45–65%, and Fats between 20–35%. So I figured these hard numbers would better help you visualize. Figure extracted from “Plotkin, A. Molecular and Clinical Nutrition Section, NIDDK Scientific Meeting. “Metabolic Flexibility: Using Indirect Calorimetry to Find the Holy Grail.” February 2021

Not bad right? In fact, this ratio even fits within the US Department of Agriculture Dietary Guidelines. So, what gives? Let’s take a closer look:

Figure extracted from: “Plotkin, A. Molecular and Clinical Nutrition Section, NIDDK Scientific Meeting. “Metabolic Flexibility: Using Indirect Calorimetry to Find the Holy Grail.” February 2021

Ah, now it makes sense. So what’s the distinguishing factor between us and the Blue Zones? For starters, it is the prevalence of processed food in our diets!

We know that ultra-processed food drives overconsumption (10). If you haven’t read my articles on this subject here they are (11, 12). This chronic overconsumption of calories can of course lead to obesity and its associated deleterious health outcomes down the line. So maybe we shouldn’t be focused on what the optimal human diet is, and be more focused on how we can achieve optimal outcomes.

One of those optimal outcomes is called metabolic flexibility. Metabolic Flexibility is the ability to match fuel oxidation with fuel availability (13). In plain English, think of metabolic flexibility as a hybrid car. A hybrid car can run on either gas or electric, just like a metabolically flexible person can run on either fat or glucose (sugar). And this my friends, is the Holy Grail.

Metabolic flexibility can be measured using an indirect calorimeter that allows us to see the ratio of carbon dioxide excreted compared to oxygen consumed. This ratio is called your Respiratory Quotient (RQ). If your RQ is 1.0 you are primarily burning carbohydrates, if your RQ is 0.7, you are primarily burning fat (14).

Why is being metabolically flexible important? Having this flexibility allows us to do the following:

  1. If you eat a high carb meal, you can burn glucose and thereby control your blood sugar (your RQ value should be close to 1.0)
  2. If you eat a high fat meal, you can burn fat rather than storing it (RQ should be close to 0.7)
  3. If you are sleeping/fasting, you can burn fat instead of having sugar cravings (RQ should be close to 0.7)
  4. If you are exercising, you can burn either fats or glucose based on the activity

So this is the ultimate superpower. If you are metabolically flexible, it doesn’t matter the situation or the type of food you have eaten, because your body will be able to adapt and use said fuel for energy based on your activity state. Unfortunately, we know that obese individuals have problems switching fuel sources based on RQ data demonstrating elevated glucose burning and reduced fat burning several hours after a meal (15, 16, 17).

Figure extracted from Muoio, 2014

You can see from this diagram that a metabolically flexible individual should be using primarily carbs immediately following a meal (RQ close to 1.0). Then, as time progresses, there is a robust switch to burning fat (RQ close to 0.7). So a metabolically flexible individual can immediately burn the carbs from their meal, and then when that process is over, they can switch over to burning their body fat to fuel the rest of their day! On the other hand, a metabolically inflexible person is stuck in metabolic purgatory and is unable to straight up burn either carbs or fats.

Why is this metabolic purgatory a problem? Well this leads to poor glycemic control, because these individuals are unable to fully utilize the carbohydrates they eat. Thus, these individuals will have higher and more rapid blood sugar crashes/spikes, making them highly dependent on carbohydrates as a fuel source (major craving alert; 19). Yet, the real problem is quite evident: If you are metabolically inflexible, you are unable to fully burn the carbs and fats you eat. What happens when you eat something and can’t use it for energy? You store it of course. Thus starting a vicious cycle of increased energy consumption and increased energy storage. This becomes a problem, because sooner or later, your fat cells can’t take in any more energy, so your body ends up shoving the extra fat around your organs (ectopic fat deposition…aka visceral fat). This could be covered over several posts, but if you have ever heard of Non-Alcoholic Fatty Liver Disease, this is an example of ectopic fat deposition. This ectopic fat is highly inflammatory and leads to various negative health outcomes down the line (20, 21).

In part 2 of this article I will cover some strategies we can use to foster metabolic flexibility, so we can take back our health.

I hope this article helps you see that maybe we should not be focusing as much on whether high carb or low carb is the best diet out there (just cut out the crap for the time-being). Instead, we should be focusing on how we can develop metabolic flexibility, so it doesn’t matter the situation we find ourselves in, because our body will be able to burn the fuel we eat and adapt to our current activity level.

  1. “Longevity, The Secrets of Long Life”. National Geographic Magazine. November 2005. Archived from the original on 2017–05–30. Retrieved 2017–04–03.
  2. Willcox DC, Scapagnini G, Willcox BJ. Healthy aging diets other than the Mediterranean: a focus on the Okinawan diet. Mech Ageing Dev. 2014 Mar-Apr;136–137:148–62. doi: 10.1016/j.mad.2014.01.002. Epub 2014 Jan 21. PMID: 24462788; PMCID: PMC5403516.
  3. Lindeberg S, Nilsson-Ehle P, Terént A, Vessby B, Scherstén B. Cardiovascular risk factors in a Melanesian population apparently free from stroke and ischaemic heart disease: the Kitava study. J Intern Med. 1994 Sep;236(3):331–40. doi: 10.1111/j.1365–2796.1994.tb00804.x. PMID: 8077891.
  4. Trichopoulou A, Vasilopoulou E, Georga K. Macro- and micronutrients in a traditional Greek menu. Forum Nutr. 2005;(57):135–46. doi: 10.1159/000083777. PMID: 15702596.
  5. Kang-Jey Ho; Belma Mikkelson; Lena A. Lewis; Sheldon A. Feldman; C. Bruce Taylor (1972). “Alaskan Arctic Eskimo: responses to a customary high fat diet” (PDF). Am J Clin Nutr. 25 (8): 737–745. doi:10.1093/ajcn/25.8.737. PMID 5046723. Retrieved 7 March 2014.
  6. Buettner, Dan (2012–11–06). The Blue Zones, Second Edition: 9 Lessons for Living Longer From the People Who’ve Lived the Longest. National Geographic Books. ISBN 9781426209499. Archived from the original on 2016–03–28. Retrieved 2015–09–22.
  8. Last & Wilson. Low Carbohydrate Diets. Fam Physician. 2006 Jun 1; 73 (11): 1942–1948
  9. D.A. KesslerThe End of Overeating: Controlling the Insatiable American Appetite. Rodale Inc. (2009)
  10. •Hall, Kevin D. “Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: A One-Month Inpatient Randomized Controlled Trial of Ad Libitum Food Intake.” 2019, doi:10.31232/
  13. Goodpaster, B. H., & Sparks, L. M. (2017). Metabolic Flexibility in Health and Disease. Cell Metabolism, 25(5), 1027–1036.
  14. Jequier E, Acheson K, Schutz Y. Assessment of energy expenditure and fuel utilization in man. Annual review of nutrition. 1987 Jul;7(1):187–208.
  15. Kelley DE, Mandarino LJ. Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. Journal of Clinical Investigation. 1990;86:1999–2007.
  16. Kelley DE, Mokan M, Simoneau J, Mandarino LJ. Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest. 1993;92:91–98.
  17. Kelley DE, Simoneau JA. Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. J Clin Invest. 1994;94:2349–2356.
  18. Muoio, D. M. (2014). Metabolic Inflexibility: When Mitochondrial Indecision Leads to Metabolic Gridlock. Cell, 159(6), 1253–1262.
  19. Logan, Samantha L., and Lawrence L. Spriet. “Omega-3 Fatty Acid Supplementation for 12 Weeks Increases Resting and Exercise Metabolic Rate in Healthy Community-Dwelling Older Females.” Plos One, vol. 10, no. 12, 2015, doi:10.1371/journal.pone.0144828.
  20. Paniagua JA. Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome. World J Diabetes. 2016;7(19):483–514.
  21. Reuben L Smith, Maarten R Soeters, Rob C I Wüst, Riekelt H Houtkooper, Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease, Endocrine Reviews, Volume 39, Issue 4, August 2018, Pages 489–517,



Adam Plotkin

Post-Baccalaureate research assistant in the Molecular and Clinical Nutrition Lab at the National Institutes of Health