Metabolic Flexibility – Part 3 Oxidative Capacity

This article is the third installment in the Metabolic Flexibility Series. Before proceeding, it would be a good idea to check out articles 1 and 2.

Thus far on our journey through understanding metabolic inflexibility as a key driver of poor health and modern disease, we have been introduced to how the inability of the body to effectively manage the supply and demand of various forms of energy can arise and become problematic.

As one piece of metabolic inflexibility, we have seen how insulin resistance, the inhibited response of a cell to the insulin signal, arises when lipids accumulate within the muscle tissue in stagnant droplets*. This insulin resistant condition arises when lipids cannot be effectively oxidized, resulting in their accumulation, which in turn sends a signal to the muscle tissue to lower its response to insulin (a signal to halt fat oxidation). Note: if you need a refresher, head back to articles 1 and 2. for the full story.

We also saw how insulin-resistant muscle tissue plays a role in systemic metabolic dysfunction. When the muscle tissue becomes insulin resistant, it can no longer do its job taking in glucose when it is elevated in the bloodstream. Because of this, the pancreas must release more insulin, causing a hyperinsulinemic state to override the muscle tissue’s insulin resistance. At this point, the body is in a vicious cycle that is increasing insulin-resistance of the muscle tissue and continuous production of insulin from the pancreas.

From a systemic perspective, tissues throughout the body are exposed to uncontrollable blood sugar and rising insulin levels. To name problems arising in just two other tissues:

• For adipose tissue, the chronic insulin “on” signal means it is continuously taking in energy to store as fat, leading downstream to excess fat accumulation and obesity.
• For the liver, this means it is continuously taking in energy to convert to fat, leading downstream to fatty liver and the overproduction of lipoprotein particles, a major hallmark of atherosclerosis and cardiovascular disease.

At this point, we have a strong idea of why metabolic inflexibility is dangerous. We also have begun to get clear on actions we can take to improve our metabolic flexibility by enhancing the body’s insulin sensitivity.

Today, we will continue by focusing on how we can improve our metabolic flexibility by enhancing the body’s fatty acid oxidative capacity. As we do so, we will walk through how our actions lead directly to the (in)ability of our muscle tissue to effectively oxidize the lipids that enter from the bloodstream, which you’ll remember is crucial because if these lipids cannot be effectively oxidized, then they tend to build up in stagnant pools within the muscle tissue and go on to cause downstream dysregulation and dysfunction via insulin resistance.

However, before jumping straight into this topic, I first wish to take a bit of a side trail to bring in an additional perspective. My hope is to get you introduced to this perspective in this article so that as we finish up our journey in the next and last installment to this series, we can step back and see the big picture.

So with that, I want to draw your attention to metabolic (in)flexibilty from a new perspective – as it plays a role in the overall balance of energy the system – that is, thinking about how the amount of energy that enters the system is balanced with the amount of energy leaving the system and the amount of energy accumulating within the system.

I will be drawing our attention to this energy balance within two specific systems:

1. the body, as a whole system
2. the muscle tissue, as a sub-system

Before we continue, I need to address a question that may arise shortly. We are about to get a bit technical in regard to some fairly simple algebra and you may start to wonder about why we should give any cares about an energy balance equation.  Let me make this clear upfront.

It matters because energy balance is a primary decision-making model used by most individuals to make healthy decisions. When it comes to deciding what to eat or how to exercise, it is ingrained in our society to call upon this idea of balancing energy – which usually leads to eating less or choosing low-calorie foods and exercising longer or harder to burn more calories.

We are going to dig into this concept because, if we are going to base our decisions on a model of energy balance, then it is a good idea to understand what the model really means – and, spoiler alert, there is much more information contained within the model than is typically extracted to advocate for the advice to simply eat less and exercise more to burn more calories.

Energy Balance

I can assume we are all familiar with the concept of energy balance, as it is one of the primary models of health used by our population. To make sure we are all on the same page, here’s a quick overview:

Since energy can neither be created nor destroyed, whatever energy enters a system must be accounted for by energy leaving the system or by energy remaining within that system:

Energy In = Energy Out + Change in Internal Energy

It follows that if we wish to change the internal state of energy within our bodies, we can think about how much energy is consumed and how much energy is expended:

Energy In – Energy Out = Change in Internal Energy

One more way to look at this: if we wish to change the internal energy stored within the body (lose weight), then we can think about taking less energy in, or expending more energy:

(-) Change in Internal Energy = (-)Energy In – (+)Energy Out

While we could play around with this equation for ages (a game I greatly enjoy playing), today, I want to draw our attention to the Energy Out term as it relates to our topic – that of oxidative capacity.

To start us off, let’s get clear on exactly what this energy out term means.

Based on what is generally taught in weight loss 101, energy out is a matter of two factors:

• Basal metabolic rate – how much energy you burn at rest
• Exercise – how much extra energy you burn during exercise

As our equation shows us, if the problem is the accumulation of excess energy, then part of the solution is increasing the energy out term, driving the system towards a negative energy balance. This simple picture helps individuals understand that even at rest, the body is burning calories, and that if they want to burn more calories, then they need to exercise.

So, is this true? Does the energy out term of energy balance tell us that all we need to do is exercise more to create an energy deficit and burn through excess fat?

You can probably guess that my answer is no, and you would be correct. As I stated above (and as I explain in much greater depth over here), there is much more to energy balance than is preached to the public, and if we want to make healthy decisions, we need a better understanding of what it really means.

To gain this understanding, let’s head back to our model of metabolic inflexibility, this time keeping in mind our model of energy balance.

Looking back at metabolically inflexible muscle tissue – with our new perspective

While the model of calorie balance that is commonly taught to the public isn’t entirely inaccurate, it does oversimplify the reality that is the complexity of the system. Because, as we’ve seen in this series, the system that is the human body and its interaction with the world is both complex and dynamic:

• complex: multiple variables are interacting, impacting each other via innumerable mechanisms
• dynamic: changing over time – one snapshot at one point in time of the functioning of these many variables may be completely different than a snapshot taken later on

Therefore, simplifying it down to the idea that you have a metabolism that will burn a certain amount, and you can add to that by exercising more – well, that’s not going to cut it anymore.

To see why and to help us move forward with a stronger approach, let us go back and walk through the same pathway from the last two articles, this time focusing on intramuscular lipid accumulation – that is, the buildup of lipid in muscle tissue when an energy imbalance occurs due to impaired fatty acid oxidative capacity.

Starting back at the beginning, given that there is a stream of lipid energy entering the muscle tissue, then this tissue needs to be able to effectively oxidize it. That is, the muscle requires the capacity to balance the amount of fat that flows in with the amount that is oxidized (used up to synthesize ATP).

When the muscle tissue loses the ability to oxidize energy, that energy can build up within the tissue in stagnant lipid droplets*. As this pattern continues, the pool of stagnant energy can serve as a strong signal to that tissue that something is wrong, and the muscle tissue will then respond in an attempt to fix the issue.

As we saw in the previous two articles, this stagnant lipid pool* is a significant piece of a broken system that is the progression of insulin resistance, and in turn, the progression of poor health and modern disease.

Tying in our energy balance perspective, we see this as an issue of a positive energy balance (lipid accumulation) driven by a decreased energy out term.

Moving forward through the progression towards systemic insulin resistance, let’s jump ahead a few steps as this lipid accumulation leads to insulin resistance in the muscle tissue, which leads downstream to a system in which:

1. Blood sugar is elevated (hyperglycemia) because insulin-resistant muscle tissue is not taking up glucose
   • Which means that components throughout the entire body (proteins, cells, etc.) are being exposed to high concentrations of glucose, putting them at risk to be damaged.
2. Insulin levels are elevated (hyperinsulinemia) because the pancreas is releasing extra insulin to overcome the insulin-resistant muscle tissue
   • Which means that the body is in a strong pro-energy storage state and that energy is being diverted towards fat storage

Let’s pause and take a look at that last point:

• Insulin levels are elevated (hyperinsulinemia) because the pancreas is releasing extra insulin to overcome the insulin-resistant muscle tissue
  • Which means that tissues throughout the body are in a strong pro-energy storage state and that energy is being diverted towards fat storage
  • Which means that adipose tissue is taking in extra energy to store as fat, and that it is releasing less of its stored fat

Let’s pull our energy balance equation into this picture of a different system – that of the adipose tissue and its interaction with the bloodstream. If energy is being driven into storage in adipose tissue and adipose tissue is unable to release this fat, then from the perspective of fat building up in adipose tissue:

We see the same thing – a positive energy balance as fat accumulation in adipose tissue.

A note here that I ask you to pay attention to: in this particular pathway, this accumulation of fat is not caused by eating too much. Moreover, it is not caused by an inability for us to consciously calculate how much we should be eating and how much we should be exercising. Rather, it is a matter of the inability of the muscle to effectively oxidize fats that progressed to system-wide dysfunction and resulted in excess fat accumulation.**

Which leads us back to our primary focus of today’s article: making decisions based on improving the ability of our muscle tissue to effectively oxidize lipids so that they do not build up in stagnant pools that progress towards systemic insulin resistance and the many downstream effects of it.

Healthy Decision-Making: Metabolic Flexibility and the Ability to Effectively Oxidize Fats

Since our ultimate task is to learn to make healthier decisions, a good course of action would be to understand how our decisions lead to the ability of our tissues to oxidize lipids, so that we can make decisions that improve, not hinder, our body’s ability to utilize the energy contained within lipids for essential functions, and to effectively burn off any excess lipid burden.

That is – we can examine how our actions lead to improved fatty acid oxidation so that we can help our muscle tissue, and in turn, the body as a whole, achieve lipid balance and the many other aspects of good health that go along with it.

What we need to pay attention to is, every time we buy groceries or prepare a meal, what are the questions that we are considering as we make the decision of what to eat? Moreover, as we go throughout our day making considerations for any activities, what are the factors we are considering as we make specific decisions regarding:

• whether or not to exercise
• which exercises to do
• how active we want to be all day long
• when to eat

… all as they relate to the body’s ability to effectively oxidize fats.

Traditionally, the advice on how to manage the energy out portion of an energy imbalance is simply to exercise more to increase the energy out term. But given what we now know, can we do better?

Let’s wrap up this article by walking through how our actions tie into the ability of our muscles to oxidize fatty acids. To do this, let’s journey to the site of fatty acid oxidation and ATP synthesis: mitochondria within the muscle cell.

The mitochondria is a double-membraned structure, and combined with the enzymes in the surrounding area, take a fatty acid molecule, strip away the atoms, further breakdown the atoms into protons and electrons, and use this energy to synthesize ATP molecules. Once these ATP molecules have been produced, the body can use them to perform various functions (e.g. muscle contraction).

A fatty acid molecule goes through a number of steps as it is broken down to produce ATP, but the most important for our discussion is the electron transport chain. In this brilliant design of nature, a derivative of that fatty acid molecule is passed along a series of complexes that strip away protons and electrons as it creates a pump that will serve as mechanical energy to synthesize ATP (***trust me, this one is worth another note).

This series is composed of an intricate balance of steps – and unfortunately, one that is prone to producing errors. As these molecules are passed along the chain and protons and electrons are stripped away, the production of highly unstable atoms is created (free radicals), and there is a tendency for leakage of these unstable, highly reactive free radicals to leak out of the chain and into the surrounding area.

Fortunately, nature has beautifully designed the system to be able to manage these free radicals with antioxidants. Antioxidant molecules interact with free radicals and neutralize them before they can go on to cause damage.

However, if this system becomes unbalanced, then these “free radicals” can build up and go on to serve as a signal to the cell that something is wrong. We are familiar with the cell’s reaction to this signal: insulin resistance.

Understanding this basic cell physiology, we can now ask, How do we make sure that this system remains (or becomes) balanced so that it can function as is necessary to effectively oxidize lipids?

Let’s walk through a few potential solutions.

One way to manage this imbalance of free radical production is by giving the mitochondria what it needs to neutralize free radicals: antioxidants. Antioxidants can come from two sources:

• the foods we consume
  • this is one we are all familiar with: the advice to consume antioxidant-rich foods (or supplements) has been widely accepted from the general public (although this may only be the case because it has something to do with drinking more wine)
• produced internally
  • the body does not get all of its antioxidants from external sources; rather, a better way to think of this is that the body produces its own antioxidants, a supply of which is supplemented by external sources. The idea here – we could send our muscle tissue the information it needs to be able to produce more of its own antioxidants

A second way to manage this – make the process more efficient, leading to the release of fewer free radicals, via:

• the foods we consume
  • the quality of the foods we consume significantly impact the flow of energy through this system
• the structure and function of that machinery
  • decades of research have demonstrated that mitochondria are no static structures (see references) – they are constantly adapting to meet metabolic needs when given the proper cues. The idea here then becomes to send the proper cues to our cells to improve the efficiency of our mitochondria

A third way to manage this – give your muscles a break from burning glucose and let them learn to burn fat

• remember a key design feature of the cell: if glucose is present, insulin will be released to signal to the cell to halt fatty acid oxidation and instead focus on glucose oxidation. This means that if glucose is present, the cell will not be able to manage its load of lipids.
  • this can be thought of in two ways: on one level, we can think about turning off a “glucose” switch and allowing our muscle tissue to oxidize lipids
  • going one step further, we can think about teaching our muscle tissue to better oxidize lipids by forcing them to burn lipids instead of glucose. This is an epigenetic process – one in which the expression of lipid oxidation genes is upregulated to allow for a higher capacity to oxidize lipids.

Now, given these three ways we can think of improving our muscle tissue’s capacity to oxidize fatty acids, what are some specific actions you can take to make this a reality?

To be able to thoroughly answer this question, it would take an entire book – something I am not willing to write this afternoon. If you do happen to find this particular pathway interesting, I recommend that you head out and do your own research on specific ways in which fatty acid oxidation can be improved.

For today, to get you started with that answer, let’s look at the three key practices of The Reprogramming Process as they relate to this specific situation:

1. Eat real, whole foods and avoid industrial not-so-foods

2. Move your body regularly and dynamically

3. Practice a balance of stress and rest

Eat real, whole foods

• Real, whole foods are often antioxidant-rich. An easy method of aiming for those higher in antioxidants: aim for colorful vegetables. The pigment in these (along with other phytochemicals) travel from your mouth, to your digestive system, through the bloodstream, and to your muscle to serve as antioxidants.
  • The beneficial effects of plants go even further, beyond the delivery of antioxidants. For example, sulforaphane, a phytochemical found in cruciferous vegetables (e.g. kale and broccoli), provides a number of protective benefits for both the cell and the mitochondria due to its multi-level effects on the ability to perform the many steps of lipid oxidation (see references 9 and 10 for more information).
• Real, whole foods also deliver high-quality energy in a controlled fashion. Because of their complex structure, they are broken down in the digestive tract slowly and carefully, resulting in a controlled release of energy into the bloodstream and a modest amount of energy entering each tissue.

Avoid industrial not-so-foods

• INSFs deliver energy in strong doses. Because their structure is not complex (INSFs are the product of a number of ingredients, many of which are highly refined forms of energy), the energy-containing molecules (e.g. lipids and glucose) are dumped into the bloodstream from where they make their way to our tissues and towards our mitochondria.
• INSFs often deliver extra burdensome chemicals and poor quality forms of energy that negatively impact the ability of our cells to perform oxidative functions.

Move your body regularly

• We can think of this one at two levels. The first is the level that we all are familiar with: moving our bodies regularly is a good way to burn through the pool of lipid, thus increasing the energy out term and leading to a greater balance of lipids in the muscle tissue.
• Going even deeper now, moving your body serves as a signal to your muscle tissue to increase its ability to oxidize lipids. When we regularly engage in low-intensity aerobic efforts, the body burns through a high proportion of lipid energy (as opposed to glucose, which is used at higher intensities). This serves as a signal to your muscles to increase the ability to oxidize lipids which leads to:
  • enhanced ability of the cell to synthesize their own antioxidants
  • increased number of mitochondria (see references 1-3)
  • enhanced structure of the mitochondria to more efficiently oxidize lipids (see references 1-3)

Move your body dynamically

• By varying the ways in which we move our bodies, we ensure that the various systems supporting the health of our bodies receive a mix of signals that lead to different sorts of beneficial adaptations.
• Above, I discussed the benefits of longer bouts of aerobic exercise. This is benfecial because it helps train the body to more efficiently oxidize lipids (among other positive benefits  to other systems – e.g. the cardiovascular system)
• You can also consider strength training and high-intensity interval training. This form of exercise provides a strong signal to the muscle to improve by putting it under a high load of stress. Importantly, the short period of time does not over-stress the muscle.

Practice a balance of stress…

• Let me get more technical here about beneficial adaptations that occur when we exercise. A design feature of nature is that biological systems (e.g. the human body) respond to stress with adaptations – that is, they tend to improve when put under a stress.
  • understand that this has to be the case for living systems to continue living. If these systems cannot respond with improvements to a stress, then that stress would kill them off.
  • What does happen is that the stress signals to the biological system to adapt – to become better at responding to that stress so that the next time it arises it is not life-threatening and can more easily be overcome
• What this means for us is that to improve our bodies functioning, we need to strategically apply stresses to it to initiate beneficial adaptations
  • Exercise is the best way to do this – stress the body by putting it under a physical load, whether it be a sprint, lifting a heavy object,  or moving for long periods of time

… and rest

• To finish up this train of thought, there is an essential yin to the yang that is stress – and that is the need to rest following the stressful period.
  • It is not enough to stress a biological system – you then must allow the system to recover. The system needs time to respond to the stress signal, repair any damage, and create the change it needs to become even stronger.
• What this means for us is that to improve the functioning of our bodies, we must balance out stresses (like exercise) with recovery periods

This may look like doing one short sprint workout, two weight lifting sessions, and 3-4 longer & slower aerobic workouts in a week to “stress” the body, combined with:

1. plenty of sleep
2. rest days
3. planned restorative sessions, such as gentle yoga or meditation

Wrap up thoughts

In this article, I took you through metabolic (in)flexibility from an oxidative capacity (or energy out) perspective. As we saw, when muscle tissue is unable to effectively oxidize lipids, a positive energy balance is created and lipids accumulate in stagnant lipid droplets in the muscle tissue.

While this is an important piece of good health, we must take care to remember that it is only one piece. The big picture that is good health extends much further, including other aspects of the metablic inflexibility pathway (e.g. insulin resistance, hyperinsulinemia, etc.), as well as whole other pathways that we could be discussing.

Given that our goal is, ultimately, to make the healthiest decisions for our own bodies, it is important to keep in mind that this is one piece of a large, complex, dynamic system. As we go about the process of learning to make healthier decisions, it is important that we work to keep all of this in mind. As we do so, it is helpful to have specific frameworks for combining all of this information in simple, yet still accurate representations that are (most importantly) useful for making effective healthy decisions.

Thus, to finish up this series, I want to combine everything that we have discussed into a framework that we can use to make healthy decisions – that is, we are taking a step back to see how this all ties into The Reprogrammed Systems Model.

When you’re ready, I’ll see you over there.

Notes

*”stagnant lipid droplets” – I made this distinction in the first article and I will take care to make it again. There is a big difference between 1. the accumulation of lipid in muscle tissues caused by an inability to oxidize lipids and 2. the buildup of lipid in muscle tissue as an adaptation to endurance exercise patterns. In (1), the lipid accumulates due to a failure to oxidize lipids, resulting in the buildup of lipid in stagnant droplets – that is, droplets that do not undergo a high flux and instead … In (2), these lipid droplets are more dynamic – lipid is routinely being delivered to the muscle and is being routinely oxidized. For more, see reference 8 for a full review.

** An important message that I will never stop explaining is that there are a number of pathways by which dysfunction can arise in the body. Unfortunately, because of our reductionist-based scientific culture, there is a tendency to argue over which pathway is the “correct” pathway – for example, does insulin resistance lead to obesity, or does the problem begin with accumulating excess fat which leads to insulin resistance. This “right vs. wrong” approach is not helpful; rather, what is helpful is to understand that there are multiple pathways to dysfunction, and that these pathways intertwinse in a complex, dynamic function.

*** Electron transport chain is, in my opinion, one of the most remarkable designs of nature. Check it out here and prepare to be amazed.

References

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