Lipid Metabolism & Its Dynamic Response to Exercise – Part 2

In part 1 we introduced the topic of lipid metabolism and its potential to improve exercise performance. Lipids represent the biggest reservoir of stored energy in the body and at low to moderate exercise intensity they are the main fuel type, however, it does beg the intriguing question as to why fat burning or fat oxidation falls off quite dramatically at higher intensities. Our aim in this series is to explore the latest scientific literature to find out how we may extend our fat oxidation capability (that is, how efficiently we burn fat) for longer and at higher intensities and thereby improve exercise performance.

Lipid Reserves & Distribution

So, first up, let’s take a look at Table 1 to see how our lipid reserves are distributed around the body.

Table 1. Characteristics of fatty acid and TG metabolism compared in adipose tissue, skeletal muscle and liver (Frayn et al 2006)
  Adipose tissue Skeletal muscle (at rest) Liver
Input LP–TG ~ 45 g/day NEFA ~ 20 g/day NEFA ~ 20 g/day
  NEFA ~ 5 g/day LP–TG ~ 10 g/day Remnant-LP–TG ~ 25 g/day
      DNL ~ 1 g/day
Stimulation of uptake Feeding/insulin Fasting (high NEFA supply) Exercise Delivery
Typical whole-body TG store 15 kg 300 g 100 g
Half-life of store 250 days 24 h 100 h
Lipolysis of TG store HSL-stimulated lipolysis HSL? Unknown
  ATGL – basal lipolysis    
  MGL – monoacylglycerol hydrolysis    
Releases mainly NEFA into plasma FA for oxidation FAs re-esterified in ER and released as VLDL-TG
Quantitative data involve some estimates and should be taken as representative only. ER, endoplasmic reticulum; FA, fatty acids; LP, lipoprotein; MGL, monoacylglycerol lipase; TG, triacylglycerol; DNL, De Novo Lipogenesis

We can immediately see that adipose tissue at approximately 15kg is by far the largest reservoir of lipids. Adipose tissue is found mainly on the upper body, particularly around the stomach. The other two areas where lipids can be found are skeletal muscle and the liver. What we need to understand is that these stores are very active. Lipids are in a constant state of flux moving between adipose tissue, liver and muscles which we shall now examine in more detail.

Lipid Exchange & Cycling

The continual flow of NEFA and TG between adipose, muscles and the liver is illustrated in Figure 2. The turnover of plasma NEFA is rapid with a half-life of only 4-5 minutes (Frayn et al 2006). Dietary fat is broken down into TG and packaged in lipoproteins known as chylomicrons in the small intestine. Chylomicrons, which have a short half-life of around 5 minutes, deliver TG to tissue expressing the enzyme, lipoprotein lipase (LPL) which is found in adipose tissue, cardiac and skeletal muscle.

LipidExchange

Figure 2. Lipid exchanges between gut, adipose tissue, skeletal muscle and liver. Note that adipose tissue LPL also releases NEFA into the plasma, making further fatty acids available for uptake by muscle and liver. ER, endoplasmic reticulum; FA, fatty acids; Ox, β-oxidation. (Frayn et al 2006)

In the fed state, LPL is upregulated at adipose tissue by the action of insulin and this leads to storage of TG and a consequent reduction in circulating NEFA. In contrast, NEFA circulation increases during the fasted state thereby providing a readily available source of energy for those tissues such as cardiac and skeletal muscle that demand it.

Frayn et al (2006) estimate that chylomicrons release up to 2/3 of their TG-payload, before making their way to the liver with the remainder (approx. 20g per day). Remnant chylomicrons and TG along with NEFA are recycled in the liver and released in very low-density lipoproteins (VLDL), which have a half-life of approximately 5 days (Table 1). Apolipoproteins and cholesterol are important constructs in the cargo-carrying structure of lipoproteins and as TG is extracted from VLDL’s their proportion or density steadily increases and VLDL’s transition to low density lipoproteins (LDL’s). NEFA’s bound to albumin or TG packaged within lipoproteins form part of a TG-NEFA cycle between adipose, liver and muscles and the flux of this cycle is determined by dietary inputs and other factors which we will examine.

So, how does this TG-NEFA cycling or flux respond to exercise? Let’s take a look.

The Dynamic Response of TG-NEFA Cycling to Exercise

A well-designed study by Wolfe et al (1990) serves as a useful introduction into the normal functioning of the TG-NEFA cycle. The investigators utilised tracer-isotopes in five healthy volunteers to accurately track the movement of NEFA as they appear and disappear within the changing flux of the TG-NEFA cycle in response to exercise.

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Figure 3. Percent re-esterification of fatty acids made available via triglyceride hydrolysis (Wolfe 1990)

During rest up to 70% of NEFA are re-esterified (Figure 3), however, this reduces down to 25% within the first 30 minutes of exercise. Another dramatic shift in NEFA flux is seen at the end of exercise when re-esterification rises above its pre-exercise level to 90%. During rest a high proportion (over 70%) of NEFA are re-esterified; this constant cycling means the body is primed to respond rapidly to fluctuating energy requirements as illustrated in this study when re-esterification drops to 25% following the start of exercise. This means fatty acids can be delivered quickly for oxidation by working tissues. The authors estimate the energy cost of this cycling as less than 2% of total energy expenditure at rest and this drops to below 0.5% during exercise. They argue that ‘the benefit afforded by a high rate of TG-NEFA cycling at rest in terms of regulation of substrate availability is thus accomplished economically in terms of overall energy expenditure.’

Upregulation of TG Hydrolysis to Meet Increasing Energy Demand

At the same time that NEFA re-esterification is reduced, TG hydrolysis (that is the breakdown of TG to release NEFA) is tripled (Figure 4).

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Figure 4. Rate of appearance (Ra) of glycerol and NEFA at rest, in exercise, and in recovery (Wolfe 1990)

Figure 5 below illustrates how TG hydrolysis combined with reduced NEFA re-esterification serves to amplify the total pool of NEFA made available for oxidation. This ensures lipid energy supply keeps well ahead of energy demand, even at higher intensities. This begs an intriguing question; if fatty acid supply is not impeded at higher intensity why is fatty oxidation reduced. In other words, there is plenty of fuel, why is it not being used. If we can answer this question, then we begin to identify a clear opportunity to improve performance, so that we can exercise for longer at a higher intensity using fat as our main fuel source.

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Figure 5. Comparison of rate of appearance of NEFA (o) with total fatty acid oxidation (o) as determined by indirect calorimetry (Wolfe 1990)

The authors conclude that ‘TG-NEFA plays an important role in enabling a rapid response of fatty acid metabolism to major changes in energy metabolism’ which is evidently the case in the five healthy individuals studied. This study illustrates unequivocally the dynamic nature of TG-NEFA in response to exercise.

In part 3 we’ll be looking at how we can optimise our fat burning capability for performance.

References

1        Frayn KN, Williams CM, Arner P. (1996) Are plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases? Clin. Sci. 90:243–53

2        Frayn KN (2010) Metabolic Regulation: A Human Perspective, 3rd Edition; Wiley-Blackwell

3        Frayn KN. Adipose tissue as a buffer for daily lipid flux. (2002) Diabetologia; 45:1201-1210

4        Frayn KN,  Arner P,  Yki-Järvinen H (2006) Fatty acid metabolism in adipose tissue, muscle and liver in health and disease. Essays in Biochemistry; Chapter7:4289-103

 

5    Wolfe RR, Klein S, Carraro F, Weber JM (1990) Role of triglyceride-fatty acid cycle in controlling fat metabolism in humans during and after exercise. American Journal of Physiology; 0193-1849/90

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