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A Peripheral Tissue and Nutrient Based Analysis of Fuel Partitioning
by: Wen Zhang

In our quest towards the improvement body composition, there are few hard and fast rules beyond the basic ‘lift-eat-rest’ protocol. However, we can, with great confidence, count on the fact that we will gain fat while adding muscle and lose muscle while shedding fat (barring some very special scenarios). The ratio of muscle gain to fat gain (and fat loss to muscle) can be tweaked through various means. By taking advantage of certain pharmacological compounds/cocktails, it is quite possible to violate the aforementioned. Likewise, manipulation of diet and exercise schemes are powerful and perhaps more importantly, easily accessible tools. Unfortunately, there is no detailed user guide describing the optimal means for utilization of diet and exercise to expedite the process of body composition refinement. Research has provided us with many clues, thankfully, and knowledge of how we can preferentially direct nutrients to certain tissues provides us with some insight towards the correct approach.

Ironically, this knowledge is largely a byproduct of the obesity boom and the accompanying rise in cases of the metabolic syndrome. While it would be preferable to have more data based upon experiments designed to optimize body composition, studying the body when it is chronically stressed (as is the case with the metabolic syndrome) can be useful for identifying key regulatory points in metabolism. We can then apply this knowledge towards our own ends. The articles in this series will be dedicated to exploration of the metabolic syndrome from a nutrient-based point of reference. We will go over some general concepts in the first two installments. Future articles will look at the detailed signaling events that underlie the physiological adaptations attributable to changes in diet and exercise. Ultimately, the goal of these writings is to explore nutrient partitioning using the metabolic syndrome as a platform – and to do so in a manner that will be readily accessible to those with a basic knowledge of biology.

An Overview of Metabolic Syndrome

The metabolic syndrome (MSX) is characterized by a host of system-wide perturbations in metabolism; the current classification of MSX includes many symptoms including insulin resistance, abdominal (visceral) obesity, hyperlipidemia, a pro-inflammatory state, hepatic steatosis (fatty liver), elevated blood pressure, and a propensity towards formation of blood clots [1-3]. Intense research has been dedicated to identifying the etiology of this syndrome, as MSX is essentially a stepping stone to cardiovascular disease, renal failure, liver failure, type II diabetes, and stroke.

Debate continues as to the root causes of MSX, and after decades of research, two observations associated with MSX have consistently stood out- a chronic low-grade inflammatory state [4-8] and defective fuel partitioning [9-17, 28, 29]. Barring any severe inborn genetic abnormalities, it is possible to induce at least some of the symptoms of MSX in an organism by subjecting it to a constant barrage of inflammatory molecules and/or by prolonged overfeeding. This certainly does not mean that MSX is always/only, induced by the aforementioned. It only means that in an otherwise normal individual, exposure to inflammatory hormones and/or fuel excess is sufficient to induce some or all of the characteristics of the MSX.

It is beneficial to view MSX in this manner for two reasons: first, it implies that MSX is (for the most part) a self-inflicted disease. This is encouraging because it implies that reversal or correction of the activities that induced MSX may be sufficient to treat it. Second, almost all pharmacological targets for treatment of MSX have a few things in common – inflammation and/or fuel partitioning. This thought pattern neatly categorizes the dozens of molecular targets for a disease of lifestyle into two systems malleable by the average person. We will first look at how defective fuel partitioning can lead to MSX.

Fuel Partitioning Defined

The term ‘fuel’ or ‘nutrient partitioning’ has rapidly gained popularity and acceptance in the last few years as a phenomenon of physiological significance. In order to understand just exactly what partitioning is, it is helpful to first introduce a model:

Fig. 1- General overview of glucose partitioning.

Figure 1 shows that glucose has four primary tissues into which it may partition. Three groups –muscle, liver, and fat- are considered to be peripheral, while the last group (brain/CNS/red blood cells) is generally referred to as central. We will focus on the peripheral tissues for now. While glucose/nutrient processing to the brain has global implications for nutrient partitioning, the scope of this article cannot do justice to this topic at the moment. For those interested, the venerable Leptin series written by Par and Spook go more in depth into this issue.

Fig. 2- General overview of lipid partitioning.

With respect to both glucose and lipid partitioning, we see that there are two main decisions that must be made: first is which tissue(s) the nutrient will enter. Second is where, within its target tissue, the nutrient goes. Thus, nutrient partitioning may be defined as the movement of nutrients between (a) tissues and (b) metabolic compartments within said tissues. In this article, we focus on glucose and lipid partitioning because these two nutrients have been shown to have significant and direct effects on cell physiology from a signaling point of view. Thus, these two nutrient classes can function alongside hormones in mediating cellular signal transduction, reinforcing the notion that food indeed can be viewed as a pharmacological agent under certain circumstances. We are ignoring amino acid flux for now, as that is best suited for another article altogether.

Figures 1 and 2 are titled ‘overview’ because they do not make any discrimination in the flux of fuels between tissues and compartments within them – they simply outline the potential routes the fuels may take without consideration for their magnitude or direction. To best understand the physiological rationale behind factors driving partitioning, it is useful to understand why partitioning should happen in the first place. We do this by looking at what goes wrong in a cluster of metabolic aberrations associated with MSX.

Zones of Compensation: Metabolic Flexibility within Genetic Confines

The peripheral tissues most heavily involved in nutrient disposal (adipose, skeletal muscle, and liver) have specific functions for which they are optimized (mainly storage, oxidation, and synthesis). They all exhibit varying degrees of plasticity in these functions when exposed to environmental factors (diet, exercise, stress, etc), and the extent to which they can adapt is thought to be limited by genetic factors that we do not yet fully understand. Within this zone of flexibility, the activities of key enzymes involved in fuel processing can be modified, and the direction and magnitude of these modifications governs nutrient partitioning. Ultimately, the body is constantly attempting to establish and maintain homeostasis in its current environment. This does not imply that the adaptations are optimal for the health of the organism – it only implies that the adaptations are designed to allow the organism to most effectively deal with its environment. 
This is an important concept to understand, because the metabolic perturbations associated with MSX are indeed beneficial when viewed in the context of an unhealthy environment. If one’s zone of adaptation is sufficiently wide that it can accommodate such changes and still maintain homeostasis (i.e. healthy blood glucose levels when constantly exposed to very high glucose levels), then the organism can continue to function with relative normalcy. If, however, the organism is exposed to the same degree of insult but its zone is insufficiently wide (due to genotype), metabolic pathologies will ensue.

Given the importance of external factors/environment in governing partitioning, it is impossible to qualitatively describe one scheme of nutrient disposal versus another without first establishing a reference point. The following section is largely optional, as it outlines a method that attempts to quantitatively represent the interaction of environment with genotype. Depending on how one processes data, this may or may not be useful. The most relevant information lies in the descriptions of what the term normal encompasses as it is used throughout this and future articles.

Positive and Negative Partitioning

As mentioned above, partitioning is deemed positive or negative depending on the environmental and physiological state an organism is in. This requires that we consider two things:

1. External factors (E) – ex: nutrient flux/feeding status, stressors, etc.2. Internal factors (I) – ex: genetic propensities.

For ease of understanding, and perhaps for future applications, it may be beneficial to represent the interactions of external and internal factors in a quantitative fashion. We will arbitrarily create a scale and assign the following values:

NE = +1; normal externalNI = +1; normal internalAE = -1; abnormal externalAI = 0 ; abnormal internal but sufficient zone of compensation

AIX = -1; abnormal internal but insufficient zone of compensation

Terms and reference points:

  • Internal implies genetic factors
  • External implies environmental factors
  • Normal internal refers to a reference human without genetic mutations that might affect metabolism. Think of this as an average healthy person with all measurable physiologic parameters dead smack in the middle of population reference standards.
  • Abnormal internal implies one or more gene polymorphisms that are associated with a loss of metabolic flexibility (i.e. reduced secretion of leptin); it does NOT include total abolishment of a gene (i.e. complete loss of leptin)
  • Abnormal external assumes a diet that would be expected to stress the physiology of the subject into which it is introduced. This may be achieved through changes in quantity and/or composition. For our purposes, we will only consider excess and not deprivation. It may also include high stress levels, inflammatory illnesses, and other environmental factors that place a moderate amount of strain on the organism.

Here are the results of the interaction between internal and external variables in each of the five different scenarios:

1. Normal external + normal internal = +1 + 1 = +22. Normal external + abnormal internal = +1 + 0 = +13. Abnormal external + normal internal = -1 + 1 = 04. Abnormal external + abnormal internal but sufficient zone = -1 + 0 = -1

5. Abnormal external + abnormal internal but insufficient zone = -1 + -1 = -2

We will set our reference value at +2. This represents a normal person in an environment that allows maintenance of metabolic health (as assessed by different quantitative and qualitative tools, i.e. DEXA, blood chemistry panels, urine analysis, glucose clamps, etc). Values less than +2 are considered to be suboptimal, and at -1 one is in danger of developing some symptoms of MSX; -2 = bona fide MSX.

These equations make several assumptions. First, note that all abnormalities are assumed to be moderate. Moderate means that there are no severe genetic disturbances, and external stressors are not overly severe (i.e. overfeeding by 10% of required calories = moderate; overfeeding by 400% of calories = overly severe). Second, the assigned values give more weight to external factors than internal (if the model were to assign equal significance to external and internal factors, then the value of AI would equal NI). Finally, having a quantitative range between MSX and the reference value implies that certain factors act as buffers against progression towards MSX. In other words, it should be harder to induce MSX through external means in a normal person in a normal environment (+2) than in an abnormal person in a normal environment (+1). Note that in the last statement, we do not care whether or not the abnormal person can adapt to an abnormal environment, because the environment is stated as being normal (non-insulting).

These equations imply that significant metabolic disturbances (i.e. MSX) only occur when an abnormal external environment interacts with an internal environment that fails to adequately compensate. The severity of the disturbance in response to a given severity of external insult depends on the ability of the individual to compensate.

Again, it should be stressed this is only meant for use in making generalizations, and only applies under conditions of moderate external stress and internal rigidity. If one pushes external factors enough (i.e. prolonged feeding of 5x the required calories to maintain weight), then no degree of internal compensation can occur due to biological limitations (i.e. to prevent abnormalities with such a significant fuel influx would require upregulation of thermogenesis to the point where it would cook the animal, or exercise so intense that it would be counterproductive). Likewise, a severe internal defect, such as lipodystrophy due to lack of adipose tissue, will resist all attempts at correction unless the defect can be artificially repaired- in this example, this would require fat transplants.

Positive and Negative Partitioning in Context: Positive Does Not Equal Healthy

The model so far predicts that when tissues are forced to adapt and adopt functions for which they are not genetically programmed, it is because they must choose between the lesser of two evils: adapt and accept a suboptimal phenotype, or refuse to adapt, to the greater detriment of the organism. Therefore, if we wish to understand how we can optimize partitioning for health, body composition, or any other purpose, we must have some knowledge of what our target tissues are designed for, how they function under normal external (NE) + normal internal (NI) conditions, the extent to which they can be pushed, and the consequences of too much (or too little) pushing. What follows is only a rough overview; more details will be provided in future articles.

Preferred functions of skeletal muscle, liver, and adipose with respect to nutrient disposal under NE x NI

Skeletal muscle prefers to store glucose as glycogen, or to directly oxidize it for fuel. Only when glucose influx exceeds the means of muscle to synthesize and/or store glycogen does glucose undergo transformation into fatty acids [18-21]; even more reluctantly is this synthesized lipid stored in appreciable quantities compared to adipose or even liver. Therefore, a tissue such as skeletal muscle, which is not optimized for storage of glucose as lipid, would be expected to show signs of distress if forced to stuff itself full with it – this is indeed what occurs in many cases of MSX, and is a classical symptom associated with lipodystrophic diseases [22, 22a]. Skeletal muscle is also the primary fat-oxidizing tissue, and readily takes up and uses lipids from the bloodstream. The beta-oxidative capacity of skeletal muscle is significant and adaptable, but ultimately finite. If faced with an excess, the ratio of incompletely to completely oxidized fatty acids increases; certain fatty acid metabolites may interfere with signaling pathways involved in nutrient uptake [36]. Additionally, some fatty acids will inevitably be stored, and accumulation of triglycerides in muscle is tightly linked with multiple metabolic pathologies [20-21a].

Similar to skeletal muscle, liver cells (hepatocytes) prefer to store glucose as glycogen or utilize it as an immediate fuel source. When fuel is abundant, the liver channels glucose to glycogen, stops the production and release of glucose (gluconeogenesis), and turns excess glucose into triglycerides for export to skeletal muscle (where it should be oxidized) and adipocytes (where it should be stored); towards this end, the lipogenic capacity of liver is significant [23, 23a]. Problems arise when the liver is forced to store large quantities of triglycerides [17, 23], as well as when it continues to release glucose even when blood levels are high. Moreover, if glycogen stores are full, the liver must channel glucose into fatty acid and triglyceride synthesis, and is also less capable of rapidly clearing some of the glucose (because the preferred storage compartment for glucose –glycogen- is full) [13].

Adipose tissue, in contrast to skeletal muscle or liver, is designed for storage- and to a much lesser (at least in humans) the synthesis of lipids [24, 24a]. Adipocytes are capable of using glucose as a fuel source as well, and even have the ability to synthesize glycogen, although the purpose of this latter phenomenon is unknown [25]. Overall, the function of adipocytes is to act as a buffer during times of nutrient excess, and as a reserve when exogenous fuel is scarce. If the storage function of adipocytes is disrupted when it is needed, and/or if it continues to release fuels even when the organism is well-fed, problems may arise [33].

There are two patterns observable in these profiles of liver, muscle, and fat: (1) the three tissues’ function is interdependent, and (2) things tend to go wrong when the fuel sinks within each tissue is full, forcing additional nutrients to be processed in a manner that may not be beneficial to the tissue. This implies that any time one of the peripheral tissues is prevented from depositing nutrients in its preferred compartment, injury may occur- and this would not be limited to a single tissue due to the interdependence of the three.

If it is true that full fuel sinks are partially responsible for pathological partitioning, then we should be able to improve partitioning by looking for ways to keep fuel sinks at least partially empty. For this, there are two approaches: the push model (bigger existing fuel sinks) versus the pull model (create a new fuel sink).

Fuel Sinks vs. Metabolic Engines: Push or Pull?

Because we did not evolve with an attached intravenous nutrient drip pumping fuels in the exact quantities needed for each waking moment, and because our fuel needs are often immediate and dynamic, we have developed storage compartments to pack away fuels for future use. These are our ‘fuel sinks’ and they are primarily glycogen (skeletal muscle and liver) and fat (mainly adipocytes). The compact nature of fat made it preferable during our evolution, and so we have retained that characteristic. The storage space within a single cell is limited, whether the fuel be bulky glycogen or compact fat; however, we can usually make more cells. Thus, one approach towards solving the problem of excess fuel influx is to simply increase the storage space (absolute size of the fuel sink).

Unfortunately, the tissue that is made for this purpose (adipose) is not an entirely benign entity. Adipose tissue has now gained widespread acceptance as an endocrine organ, and the source of many of the pro-inflammatory molecules that contribute to the development of MSX. Several of these adipose-derived factors also interfere with the functioning of master nutrient regulating hormones (insulin for example), and in a classical example of how nutrient-hormone interactions contribute to the loss of metabolic control that characterizes the metabolic syndrome. Aforementioned disadvantages aside, reliance of fat as a storage depot is actually a good thing from the standpoint of the other tissues. Storage of excess fuels as fat in liver, muscle, beta cells, or other locations entirely unsuited for this function leads to a metabolic nightmare far more severe than if the fat were placed where it belonged- in the adipocyte [22, 23, 29]. Furthermore, increasing the number of subcutaneous adipocytes may be relatively neutral metabolically speaking, as it is visceral fat accumulation that is appears to be most detrimental to global metabolism [8]. Thus, finding ways to increase the subcutaneous fat cell number without a concurrent proliferation of visceral fat may be of some value in ameliorating pathological partitioning associated with excessive infusion of nutrients.

Fig 3a (left) and 3b (right). Adipose = yellow sphere; skeletal muscle = red diamond; liver = green pentagon. A graphical representation of the ‘push’ model. 3a., describes the situation without compensation. 3b. describes the situation when adipose stores are stimulated to take up more nutrients. Note in 3b that more flux goes towards adipose, increasing its size, while the flux into muscle and liver are decreased, accompanied by a decrease in size as well.
Fig 4a (left) and 4b (right). Symbols are as described in fig 3; grey burst in 3b = energy sink. A graphical representation of the ‘pull’ model. 4a. describes the situation without compensation. 4b describes the situation when a new energy sink is introduced. Note in 4b that overall fuel flux into the three tissues increases, and at the same time, their size decreases. Compare figure 3b to 4b to see the general differences in the push vs. pull approach.

If pushing more nutrients into expanded adipocytes is not the best solution to our problem, we are left with the option of pulling the fuel excess out of the body. To do this effectively requires two conditions: first and foremost, there must be an outlet for energy to flow out of, and in as wasteful a manner as possible. Second, the machinery for processing of the fuels must be intact. Physiologically, the first goal can be met by increasing the conversion of energy to heat without generation of biologically useful chemical compounds which can be used to do work (i.e. ATP, GTP). In other words, uncoupling oxidative phosphorylation from ATP synthesis and/or induction of other futile cycles. The second condition necessitates an increase in the key gatekeeping enzymes that are responsible for turning nutrients into the high-energy compounds that ultimately generate ATP. If these two conditions are both met, then we will have successfully created a new sink- an energy sink- that drains into the environment (as heat loss) rather than a bodily tissue.

The pulling approach has some advantages to the pushing approach because the former attacks the problem of dysfunctional partitioning at its very core, assuming that the problem was induced by an excess of fuel. For example, if we begin with overfilled adipose tissue (particularly visceral) we see that it secretes pro-inflammatory factors known to contribute to (if not induce) global insulin resistance [29]. This decreases the ability of skeletal muscle to effectively take up glucose per unit of insulin secreted. The beta cells of the pancreas must then secrete more insulin, because blood glucose levels are under tight regulation. In such a manner, a state of inflammation and insulin resistance driven by excess fuel influx is established. Insulin resistance in this case essentially reverses the roles for which the peripheral tissues are best suited: lipid synthesis in adipose tissue is reduced, but the lipogenic effect of insulin is still maintained in skeletal muscle, as well as in liver [30-32].

To compound matters, the anti-lipolytic effect of insulin is blunted, as is its ability to stop hepatic glucose output (gluconeogenesis). Finally, insulin resistance seems to impair the ability of adipose tissue to proliferate, which limits the expansion of the very tissue that is optimized to store excess nutrients [33]. So, we end up with high circulating insulin levels, constitutively elevated lipolysis rates, high rates of lipogenesis in liver and skeletal muscle, increased glucose output by the liver (and kidneys in some cases), impaired adipocyte population expansion, and a chronic low-grade inflammatory state. This state of persistently augmented circulating nutrients coupled with an inability to properly dispose of them (i.e. no compensatory upregulation of uncoupling mechanisms to dissipate some of the excess energy) makes diagnosis of the original trigger very difficult- phenomenon that were originally responses later go on to be effectors.

Fig 5. A simplified outline of why simply pushing more glucose (or fuel in general) into adipose does not correct impaired fuel partitioning. Growth of adipose tissue is linked to increased secretion of pro-inflammatory factors (represented by purple flag) which inhibit skeletal muscle and liver glucose uptake for a number of reasons which are described in the text.

For an energy-drain method to alleviate the metabolic syndrome, the organism must be able to recover from the general state of insulin resistance on its own; this requires a functional pancreas, among other things. We must also ensure that whatever approach we take to dissipate energy does so in a manner that does not cook the organism (as in DNP overdosing, for example), or kill vital cells due to excessive ATP depletion. Additionally, the method must sufficiently upregulate free-radical neutralizing systems to deal with the excess of reactive oxygen species that accompanies an increase flow through the mitochondrial electron transport chain. A further requirement is that the approach be sustainable- that is, a treatment protocol must not induce short-term upregulation of metabolic rate but cause long-term suppression by failing to take into consideration central mechanisms of energy sensing and regulation. Finally, we must remember that some tissues are better suited than others as metabolic engines. Skeletal muscle is wonderfully efficient at oxidizing fatty acids to completion if given the proper stimulus, and its sheer quantity makes it an ideal target [36]; on the other hand, overexpression of genes that are beneficial in skeletal muscle might be detrimental in other tissues [35].

Conclusion

To summarize, we now see that optimization of fuel partitioning is of key importance in treatment of MSX. MSX may be thought of as an attempt by the body to adapt to an environmental stressor. In the short term and under the right conditions, this may actually be beneficial. For example, during starvation, insulin resistance spares amino acid catabolism and shifts the reliance of those tissues that can support it to fatty acids and ketones. In burn victims, massive hyperglycemia is needed to drive glucose into damaged tissues by sheer diffusion, and inflammation aids in fighting infection and clearing dead tissues. With chronic overfeeding, the resistance to insulin may protect skeletal muscle from being overloaded with nutrients. However, a distinction must be made between positive partitioning and healthy partitioning; the long-term effects of the former must always be viewed in the context of the environment/stressor that induces it, while the latter assumes that the stressor/environment is already conducive to the health of the organism.

Despite its multifaceted clinical and biochemical fingerprint, MSX’s etiology may be traced back to a chronic inflammatory state leading to dysfunctional partitioning, or dysfunctional partitioning leading to a chronic inflammatory state. Either way, amelioration of the impaired fuel partitioning through increasing the absolute size of the fuel sink (push), generating a new energy sink (pull), or a combination of the two, holds great promise. However, many obstacles stand in the way, as we cannot afford to thrown the system more off-balance by pushing or pulling too much (with respect to the whole body, and to a specific tissue/compartment). Correcting MSX requires that we look for ways to guide the body back into homeostasis, a theme that we would do well to keep in mind any time we attempt to harness the metabolic flexibility of the primary tissues involved in fuel handling for our own purposes.

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