Metabolic Flexibility – Part 1

The Reprogrammed Systems Models represent the human body and the impact of our decisions on its state of health.

We begin this lesson on metabolic flexibility with The Model of Poor Health and Disease Progression (aka Energy Dysregulation, Metabolic Dysfunction, and Modern Disease). It demonstrates hows energy dysregulation plays the role of the key physiological driver of poor health and modern disease.

Here’s some quick background:

The systems supporting the human body are constantly at work, performing innumerable functions that we have only begun to understand. To do all of this, the body needs energy delivered in a controlled fashion – that is, the energy supply must enter into circulation (and from there into tissues throughout the body) in a way that allows these tissues to function properly without overburdening them. Moreover, the metabolic needs of each cell, tissue, and organ must be met so that each can perform its specialized functioning.

To perform the task that is orchestrating the complex network of human metabolism, the human body has evolved networks of signaling mechanisms, including biochemical and electical signals. When regulated properly, these complex networks balance various types of fuel sources (primarily, fats and carbohydrates), controlling how they enter the body, how they are shipped and stored throughout the body, and how each tissue is using a particular fuel source.

Below is a simplified diagram of the different paths that an energy-containing molecule could travel once it enters into the body (via the digestive system). To keep things simple and most relevant to your health-conscious decisions, we will keep the focus on two categories of molecules: fats (modeled as single fatty acids) and sugars (aka carbohydrates, modeled simply as glucose).

We begin diving in with a question:

What would happen if these systems cannot communicate as nature has designed them to? That is, what would hapepen if the components within this system (e.g., tissues and organs) lose their ability to effectively signal to other components regarding their energetic needs and conditions?

The simple answer: If these systems lose their ability to communicate the energetic needs of various tissues and organs, then the functioning of these systems will be impacted.

Remember, each of these components (once again, cells, tissues, and organs) each have their own complex functions that they need to be able to perform to be able to support the health of the human body. While it can be helpful to understand this functioning of each tissue or organ, the approach we are taking (by focusing on metabolic health) is to largely ignore this functioning, for now, instead choosing to think about how the entire body functions at a higher level.

Getting back to that higher level functioning: as the cells, tissues, and organs that make up the human body lose their ability to communicate their energetic state and needs, these components lose their ability to function optimally.

This energy dysregulation has far-reaching consequences, spreading to each tissue throughout the body and contributing to the progression of poor health, and ultimately, a modern disease diagnosis.

Energy dysregulation encompasses a wide spread of general concepts and specific mechanisms. With this series, I wish to focus on one particular concept, metabolic (in)flexibility, and the specific mechanisms governing it. In this introduction article, I will focus on the bigger picture idea that is metabolic (in)flexibility, tying it into the bigger picture that is captured by The Reprogrammed Systems Models. Then, as we move through the next three lessons over the next three weeks, we will dive deeper into the technical aspects of this concept along with how they tie into the decisions you make in your own life.

My hope is that at the end of this series, you will be equipped with the information you need to be able to make healthier decisions aligned with respecting and enhancing the metabolic flexibility of your own body.

Metabolic Inflexibility

I define metabolic inflexibility as the inability of systems supporting the human body to balance energy supply and demand, given:

1. A variety of fuel sources (fatty acids, sugars, protein, ketones, etc.) and
2. Dynamic metabolic demands (sedentary vs. low-intensity vs. high-intensity activity; fasting vs. fed state)

When thinking about how this plays into The Reprogrammed Systems Model – that is, when thinking about how metabolic (in)flexibility plays into our decisions and their impact on the health of our bodies, we can think of it both internally (what is happening inside the body) and externally (what is within our conscious thought and control):

• Internally: cells sensing the body’s internal state and reacting based on the specific function of that cell
  • For example, an adipocyte (fat storage cell) will sense whether there is a high or low amount of fat or carbohydrate, and based on what it senses it will either store or release that energy as fat
• Externally: these systems will communicate findings to the brain, which may initiate a behavior to meet the needs of what is sensed internally
  • For example, to go find carbohydrate when blood sugar is low, or to go move when blood sugar is elevated

This has implications for a number of behaviors that we may be concerned about:

What we eat, for one….

• Eat a mixed meal with moderate fat and carbohydrate and the body is capable of managing both fuel sources, preferentially burning carbohydrate while storing away excess energy as glycogen and fat
• Eat a high-fat meal with minimal carbohydrate and the body is capable of utilizing fats as a fuel source for oxidation while limiting carbohydrate as a fuel source
• Eat a high-carb meal and the body will manage the large load of carbohydrate, storing away any excess as glycogen or fat.

Eating and exercise patterns for another…

• Can’t get out of the office to eat lunch… no problem, the body will just tap into fat stores to get its meal
• Go for a long run… no problem, the body will tap into fat stores to get the large volume of energy
• Play in a soccer match requiring a mix of sprints, jogging, and walking… no problem, the body will switch up between fats and carbohydrates depending on the needs of the muscle (and other tissues) at the time

Now, given this basic information about metabolic flexibility, the important question for us is, What happens when the body loses its ability to perform this function? What if certain cells (say, muscle cells responsible for utilizing fuel sources to produce energy) cannot effectively bounce back and forth between fat and carbohydrate as fuel sources?

One answer to this question comes from (ref 1):

“Maintaining a balance between energy demand and supply is critical for health. Glucose and lipids (fatty acids and ketone bodies), as sources of cellular energy, can compete and interact with each other [ref]. The capacity for an organism to adapt fuel oxidation to fuel availability, that is, to preferentially utilize carbohydrate and lipid fuels and to be able to rapidly switch between them is termed metabolic flexibility [ref]. The failure to match fuel oxidation to changes in nutrient availability is often accompanied by symptoms such as insulin resistance, ectopic lipid accumulation and mitochondrial dysfunction [ref]. Thus, metabolic inflexibility is tightly related to a series of syndromes such as type 2 diabetes (T2D), obesity, cardiovascular disease and metabolic syndrome.”

The answer to what happens when systems supporting the body become metabolically inflexible is the progression of the diseases that our modern world is all-too-familiar with, including type 2 diabetes, obesity, and cardiovascular disease.  These modern diseases arise as the systems supporting the human body lose their ability to function, which includes the inability to balance the supply and demand of diverse fuel sources – which we now know as metabolic inflexibility.

Given the consequences of the loss of the body’s metabolic flexibility, this is an important concept for us to understand. If we can appreciate the ability of our bodies to perform this important function while taking action to help it maintain this functioning, then we are one step closer to the ability to make healthy decisions and are on our way to a long, healthy life.

Now that you’ve heard the basics, let’s dig into this concept with an example that we can tie into The Reprogrammed Systems Model. We’ll begin by looking at one specific fuel source (fatty acids) and one specific component (skeletal muscle), along with how this ties into the bigger system that is energy balance throughout the entire human body.

Fat Balance in Skeletal Muscle

Fatty acids are one fuel source that may enter the muscle, which, ideally, will be used as a fuel source to create ATP, the body’s usable form of energy. In this process, fatty acids are oxidized – their atoms are stripped away to be used for ATP synthesis, while the remainder of the molecule is released as by-products (breathed out as CO2, for example).

Note that fatty acids may enter the bloodstream and make their way to the muscle from two primary sources:
– from a recently consumed meal
– from storage in adipose tissue

In a 1999 study (ref 2), it was shown that in healthy subjects, the elevation of lipid in the bloodstream resulted in an increase in the oxidation of fatty acids in the muscle. This makes sense – as fat enters the bloodstream and is driven into the muscle, the muscle shifts to oxidizing this load of fat. Thus, in healthy subjects, a fat balance is achieved in the muscle:

This isn’t the case for all individuals though. The authors of this same study, along with others (5,6) have found that metabolically unhealthy individuals are unable to maintain this same fat balance. The muscle of metabolically unhealthy subjects did not respond in the same balanced fashion, as they were unable to effectively oxidize the full load of fat entering the muscle.

During resting postabsorptive conditions, as after an overnight fast, it is generally considered that the predominant substrate oxidized by skeletal muscle is lipid, provided substantially by a high rate of uptake of plasma FFA (ref). In the current study, during fasting conditions, these patterns were reaffirmed in lean subjects. However, in obese subjects, despite rates of fatty acid uptake that were equivalent to those of lean subjects, fasting rates of fatty acid oxidation by leg tissues were significantly lower. The values for the RQ across the leg denoted a reduced reliance on lipid oxidation in obesity, such that only one-third of energy production was accounted for by fat oxidation, whereas nearly twice this proportion was found in muscle of lean volunteers. (ref 2)

To summarize from (ref 2): after a night of fasting, lipids are typically the primary fuel source utilized by muscle. This load of lipid is taken up similarly in both lean and obese subjects – that is, the rate that lipids are taken into the muscle are not different in lean vs. obese subjects. What is different is the rate that lipids are oxidized, with this study finding that lean subjects were oxidizing lipids at twice the amount.

This raises an important question: if fat is elevated in the bloodstream (which may happen due to a fast or after a fatty meal), and that fat enters the muscle but does not get oxidized, then what happens to it?

This question isn’t a difficult one. If fat is entering the muscle but is not getting used up to create energy, then that fat must be remaining inside the muscle.

When fat is stored in the muscle, it is referred to as intramuscular triglyceride (IMTG), and it has significant implications in unhealthy individuals.*see notes

The term “lipotoxity” captures the harm that arises when fatty acids are not effectively processed within the muscle.* There is a large body of research showing what happens when this excess fat builds up in the muscle, with the most significant impact being the arising of insulin resistance (ref 5-8).

If you are familiar with The Reprogrammed Systems Model, you are probably aware of where this pathway is leading. With this next section, we’ll walk through how fat imbalance within the muscle ties into the metabolic dysfunction of the entire body.

Fat imbalance contributes to system-wide metabolic dysfunction

So far, we have only discussed fatty acid oxidation within skeletal muscle. However, the muscle is constantly balancing a load of both fatty acids and sugars (glucose being the primary sugar utilized as energy). Successfully performing this balance is one piece of metabolic flexibility. As we saw above, metabolically inflexible muscle is unable to balance just one of these fuel sources – fatty acids – which leads to fatty acid build-up and lipotoxicity within the muscle.

What happens when glucose now enters the picture, which happens regularly when we consume food containing carbohydrate?

When glucose enters into circulation, the pancreas releases insulin, a signal to the entire body that blood sugar is elevated and that systems throughout the body need to act in a way to decrease that load of glucose.

For the muscle, this means:

1. take in glucose and store it as glycogen
2. take in glucose and utilize it as a fuel source to generate ATP.

But, what happens if the muscle cannot listen to insulin? That is, what happens if the muscle is deaf to the signal that glucose is elevated?

The answer is simple: if muscle tissue cannot hear the insulin signal, then it will not take in the elevated load of glucose in the bloodstream.

If muscle tissue isn’t taking in glucose, then the entire body has a problem. Elevated blood sugar is acutely toxic to tissues and other biomolecules throughout the body. This means that if blood sugar is free to remain elevated, then tissues throughout the body may be damaged or lose their ability to function altogether.

The body cannot afford for this elevated blood sugar to continue, which is why nature has designed a solution to insulin resistance: the release of even more insulin. The idea is simple – if the muscle can’t hear the signal, then a solution is simply to send out a stronger signal.

The result is that the insulin-resistant muscle will hear the stronger insulin signal, take in glucose from the bloodstream, and manage it by either storing it as glycogen or by utilizing it as a fuel source.

Now, as I emphasize in the walk-through of The Reprogrammed Systems Model, insulin is the body’s pro-energy storage hormone. The body perceives the insulin signal as a sign to:

1. Store energy, overall.
   • Lipids get stored as fat in adipose tissue
   • Glucose gets stored as glycogen in muscle or liver or as fat in adipose tissue
2. Preferentially manage the load of glucose
   • Muscle tissue halts fatty acid oxidation and instead burns glucose

This means that when insulin is elevated, the body is put in a state in which energy is diverted into storage. Most significantly, this means that lipid (and glucose, although to a lesser extent) is getting stored as fat in adipose tissue and that lipid is not getting oxidized.

Now, given our set-up with insulin-resistant muscle tissue driving a hyperinsulinemic state for the entire body, let’s think about the downstream effects. If the body is receiving a stronger signal to store energy, then the energy that is consumed will be more likely to end up in storage as fat. In this way, excess fat accumulation may occur as a hyperinsulinemic state is maintained.

At this point I would like for you to stop and think about these pathways. We began in the muscle tissue with elevated lipids unable to be oxidized, leading downstream to the current model of excess lipid accumulation. If lipids are building up in the body, what is their ultimate fate?

We could continue down this rabbit hole for the rest of the day, following different pathways to examine different sorts of dysfunction. But, to wrap things up, let’s jump to the big picture that is excess lipid accumulation and systemic insulin resistance – which includes, of course, the muscle tissue.

Given that we started in the muscle tissue with an inability to balance the amount of incoming fat with poor oxidative capacity, and that this led to insulin-resistant muscle and downstream into the pathway shown in Image 12 above, what does this mean for the system, as a whole?

What we have here appears to be a vicious cycle of insulin resistance, hyperinsulinemia, and elevated blood sugar and blood lipids. Combined, this state is known as metabolic syndrome and is at the root of modern disease, including the progression of athersclerosis and cardiovascular disease, the development of type II diabetes, and the decline of the brain as it develops dementia or Alzheimer’s disease.

A few important questions arise that would be useful to address:

• if this is a cycle, then where does it begin? what actions initiate this cycle?
• what actions feed into the progression of this cycle?
• what decisions can we make to prevent, or even reverse, this cycle?

All of these questions are important for us to ask and answer so that we can take control of our own health. With the next few weeks, we will continue digging into this idea, answering these questions along the way.

For today, I would like for you to consider what you already know about energy regulation and key healthy principles. What actions can you take to avoid these pahtophysiologic pathways in your own body?

Here are a few that come to my mind:

• regular movement along with high-intensity exercise is a great way to enhance the muscle’s ability to oxidize fats.
• consuming real, whole foods helps the body manage its own energy balance
• consuming antioxidant and polyphenol-rich foods help the mitochondria perform their functioning, enhancing their ability to oxidize fats and carbohydrates.

Notes

* IMTG is a fascinating subject with a large body of research supporting it. What I find most interesting is that lipid may accumulate in muscle for different reasons, and depending on that specific reason, the downstream effects of having these lipid droplets vary tremendously. On the one hand, there is a positive and linear relationship between the metabolic dysfunction of an individual and the amount of lipid stored in the muscle – that is, healthier individuals have less lipid stored within muscle as compared to metabolically unhealthy individuals. However, there is a different population that also has high amount of lipid stored in their muscle, and that is athletes – particularly endurance athletes. The amount of lipid stored in this active & healthy population is right up there with the sedentary, metabolically unhealthy individuals. However, these lipid pools don’t have the same lipotoxic effects. The bottomline: it is not the deposition of fat in muscle that is problematic; rather, it is the dynamics of the formation of the lipid droplets that leads to this stored fat being either pathophysiologic (driving insulin resistance) or beneficial (being used as a pool of energy to be readily available during endurance efforts).

References

1. Zhang, S., Hulver, M. W., McMillan, R. P., Cline, M. A., & Gilbert, E. R. (2014). The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility. Nutrition and Metabolism, 11(1), 1–9. https://doi.org/10.1186/1743-7075-11-10
2. Kelley, D. E., Goodpaster, B., Wing, R. R., & Simoneau, J. A. (1999). Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. American Journal of Physiology – Endocrinology and Metabolism, 277(6 40-6). https://doi.org/10.1152/ajpendo.1999.277.6.e1130
3. Freese, J., Klement, R. J., Ruiz-núñez, B., Schwarz, S., & Lötzerich, H. (2017). The sedentary ( r ) evolution : Have we lost our metabolic flexibility ? (0), 1–15. https://doi.org/10.12688/f1000research.12724.1
4. Goodpaster, B. H., & Sparks, L. M. (2017). Metabolic Flexibility in Health and Disease. Cell Metabolism, 25(5), 1027–1036. https://doi.org/10.1016/j.cmet.2017.04.015
5. Meex, R. C. R., Schrauwen-hinderling, V. B., Moonen-kornips, E., Schaart, G., Mensink, M., Phielix, E., … Hesselink, M. K. C. (2010). Restoration of Muscle Mitochondrial Function and Metabolic Flexibility in Type 2 Diabetes by Exercise Training Is Paralleled by Increased Myocellular Fat Storage and Improved Insulin Sensitivity. 59(March). https://doi.org/10.2337/db09-1322.
6. Battaglia, G. M., Zheng, D., Hickner, R. C., & Houmard, J. A. (2012). Effect of exercise training on metabolic flexibility in response to a high-fat diet in obese individuals. American Journal of Physiology – Endocrinology and Metabolism, 303(12), 1440–1445. https://doi.org/10.1152/ajpendo.00355.2012
7. Smith, R. L., Soeters, M. R., Wüst, R. C. I., & Houtkooper, R. H. (2018). Metabolic flexibility as an adaptation to energy resources and requirements in health and disease. Endocrine Reviews, 39(4), 489–517. https://doi.org/10.1210/er.2017-00211
8. Nolan, C. J., & Larter, C. Z. (2009). Lipotoxicity: Why do saturated fatty acids cause and monounsaturates protect against it? Journal of Gastroenterology and Hepatology (Australia), 24(5), 703–706. https://doi.org/10.1111/j.1440-1746.2009.05823.x
9. Estadella, D., Da Penha Oller Do Nascimento, C. M., Oyama, L. M., Ribeiro, E. B., Dâmaso, A. R., & De Piano, A. (2013). Lipotoxicity: Effects of dietary saturated and transfatty acids. Mediators of Inflammation, 2013. https://doi.org/10.1155/2013/137579
10. Rial, E., Rodríguez-Sánchez, L., Gallardo-Vara, E., Zaragoza, P., Moyano, E., & González-Barroso, M. M. (2010). Lipotoxicity, fatty acid uncoupling and mitochondrial carrier function. Biochimica et Biophysica Acta – Bioenergetics, 1797(6–7), 800–806. https://doi.org/10.1016/j.bbabio.2010.04.001
11. Bosma, M., Kersten, S., Hesselink, M. K. C., & Schrauwen, P. (2012). Re-evaluating lipotoxic triggers in skeletal muscle: Relating intramyocellular lipid metabolism to insulin sensitivity. Progress in Lipid Research, 51(1), 36–49. https://doi.org/10.1016/j.plipres.2011.11.003