Less Than 15mg of DHEA Exert Identical Beneficial Effects on Insulin Sensitivity as 1h of Cardio 5x Per Week. Both Effects Mediated Via Increases in Intra-Muscular DHT

Image 1: It has long been established that diabetics have particularly low DHEA levels (Loviselli. 1994), but what's the chicken and what's the egg here?

It is quite funny, sometimes you don't hear about certain supplements, (pro-)hormones, exercise-modalities etc. in years and then, all of a sudden, there are two studies on the respective topic in one week; and moreover, two pretty interesting ones! Last Friday, exactly 7 days ago, you've read here at the SuppVersity about the muscle-protective effects of low-dose dehydroepiandrosterone (DHEA) supplementation during a 5-day intense multiple-type exercise protocol (cf. "DHEA Blunts Muscle Damage During 5 Days of Combined Endurance, Strength and HIIT Training in Young Men"). Today, I have another interesting set of data for you - data which could not just shed some light onto the underlying mechanisms of the said protective effects against skeletal muscle damage, but also on DHEA's beneficial effects on insulin sensitivity.

Not younger, but leaner with a minimalist dose of DHEA?

In a 6 week trial, and thus over a more than eight times longer timespan than in the previously mentioned human study on skelatal muscle damage, Koji Sato and his (or her?) colleagues from the Ritsumeikan University, the Senshu University and the University of Tsukuba (all in Japan, as you probably already suspected) investigated the effects a low dose of DHEA (human equivalent: 0.16mg/kg per day => 10-15mg/day) supplementation on the insulin, QUICKI (=quantitative insulin-sensitivity check index) and intramuscular DHEA and DHT (dihydrotestosterone) levels in sedentary or exercised dietary obese male rodents.

Figure 1: Relative insulin levels, QUICKI, intramuscular DHEA and DHT content in obese male rodents after 6 weeks of DHEA or combined DHEA + exercise (1h, 5days/week) treatment (data adapted from Sato. 2012)

As you can see in figure 1 the effects of both 5x/week running on a treadmill (ETA: 1h) and orally administered DHEA were profound. If you compare the "exercise only" group (red) to the two DHEA groups (green and violet), you will yet notice interesting parallels. Not only were the decreases in serum insulin and the increases (=improvements of insulin sensitivity) in the QUICKI test very similar, the exercise regimen alone yielded a +56% increase skeletal muscle DHEA content and a +71% increase in DHT.

Exercise increases intramuscular DHEA & DHT...
 

Figure 2: Hormonal cascade from DHEA to DHT; all enzymatic conversions can take place on a systemic and intra-cellular level!)

At least the latter, i.e. the increase in DHT should not be news to you if you have been following the in-depth articles at SuppVersity over the past couple of months. From the Intermittent Thoughts on DHT you know that exercise in general and HIT endurance exercise in particular has been found to boost intramuscular dihydrotestosterone levels, as well. The bros, or friends of bros among you, will probably also have heard the horrific stories about creatine monohydrate leading to increased levels of DHT (van der Merve. 2009), of which every reasonable person must actually assume that they are nothing but a downstream effect of increased training loads and/or improved adaptation... I mean, think about it "paleo style": Why would the mammalian body (rodent and human appear to react alike here) increase the DHEA and, via 5-alpha reductase (cf. figure 2), the dihydrotestosterone levels in response to high volume exercise, if not as a means of adaptation?

Oral DHEA + exercise = double-whammy against obesity

The combined treatment, or I should say the exogenous support of the exercise induced changes had - and this is not visible from the data in figure 1, astonishingly profound effects on the diet induced weight gain of the lab animals. While all other rodents became fatter, those in the exercise + DHEA group remained at a steady body weight level; an observation the researchers comment as follows:

Although DHEA administration and exercise training each produced beneficial effects, 6-weeks of combination treatment were more effective for obesity. The precise mechanisms that reduced abdominal fat weight in the combination group remain unclear, yet we can propose several plausible hypotheses. 2 weeks of DHEA administration has been shown to activate fatty acid metabolism-related enzymes, such as long-chain fatty acyl-coenzyme A synthase, and to increase free CoA levels in liver (Mohan. 1998; Mohan. 1990). In addition, exercise training is  known to reduce adipogenesis via upregulation of fatty acid metabolism and increased energy expenditure (Hou. 2003). Therefore, 6-weeks of combination treatment may have promoted additive reductions in abdominal fat volume.

In other words, while DHEA increases the efficacy of fatty acid oxidation, exercise takes care of the increase in energy expenditure which is - all convictions wrt to "calories don't count" and the "calories in vs. calories out"-hypothesis aside - still a fundamental prerequisite that the fatty acids do actually get burned and are not released into circulation to be restored or replaced a couple of hours later.

"Ok, I am just ordering some DHEA, how much should I take?"

Before you head over to the online vendor of your choice to make sure you get your share of DHEA before the FDA hears that it could hamper the sales of diabetes drugs and removes it from the OTC market, I would like to remind you that despite the fact that Sato et al. rightly claim that a "combination treatment [with DHEA and DHT] may be more beneficial than either therapy alone", a cursory glance on the data in figure 1 should suffice to tell you that those additional benefits as statistically significant as they may be are just that "additional" and that exercise alone yielded about equal results, is free of negative and full of beneficial side effects (update: as long as you don't overtrain; thanks Stapedius for this important note) and does not have the same host of studies refuting its efficacy as DHEA has (Clore. 1995).

It is nevertheless intriguing that a hormone the medical orthodoxy has, more or less all of a sudden, dropped like a hot potato and declared "questionable" and "ineffective" is now, roughly 15-20 years being rediscovered... and I am pretty sure that this was not the last DHEA study you will see and read about here at the SuppVersity ;-)

References:

1. Clore JN. Dehydroepiandrosterone and body fat. Obes Res. 1995 Nov;3 Suppl 4:613S-616S. Review.
2. Hou CW, Chou SW, Ho HY, Lee WC, Lin CH, Kuo CH. Interactive effect of exercise training and growth hormone administration on glucose tolerance and muscle GLUT4 protein expression in rats. J Biomed Sci. 2003 Nov-Dec;10(6 Pt 2):689-96.
3. Loviselli A, Pisanu P, Cossu E, Caradonna A, Massa GM, Cirillo R, Balestrieri A. [Low levels of dehydroepiandrosterone sulfate in adult males with insulin-dependent diabetes mellitus]. Minerva Endocrinol. 1994 Sep;19(3):113-9.
4. van der Merwe J, Brooks NE, Myburgh KH. Three weeks of creatine monohydrate  supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players. Clin J Sport Med. 2009 Sep;19(5):399-404.
5. Mohan PF, Cleary MP. Effect of short-term DHEA administration on liver metabolism of lean and obese rats. Am J Physiol. 1988 Jul;255(1 Pt 1):E1-8.
6. Mohan PF, Ihnen JS, Levin BE, Cleary MP. Effects of dehydroepiandrosterone treatment in rats with diet-induced obesity. J Nutr. 1990 Sep;120(9):1103-14.
7. Sato K, Iemitsu M, Aizawa K, Ajisaka R. Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle. Am J Physiol Endocrinol Metab. 2008 May;294(5):E961-8. Epub 2008 Mar 18.
8. Sato K, Iemitsu M, Aizawa K, Mesaki N, Ajisaka R, Fujita S. DHEA administration and exercise training improves insulin resistance in obese rats. Nutr Metab (Lond). 2012 May 30;9(1):47. [Epub ahead of print]

Study Identifies Caffeic Acid Induced AMPK-α2 Activity Behind the Fat Burning, Insulin-Sensitizing & Life-Extending Effects of Coffee. Plus: Why Creatine & Coffee Don't Mix!

Image 1: I've got news for you: Real coffee does not come in brown sterophome cups ;-)

Ever since Starbucks came out with the "McDonald's version" of what used to be the drink of the popes and kings, coffee has gotten sort of a bad reputation. It is supposed to "burn out your adrenal glands" (I bet most people who support this hypothesis don't even know where the adrenal glands are situated), derive you of  vital nutrients and water, reduce insulin sensitivity, give you palpitations and high blood pressure, ... I guess, you know the whole litany. If we take a closer look at the contemporary scientific consensus, many of these arguments against your 2-3 cups of coffee per day lack any scientifically verified basis. Others apply only if you (ab-)use the uber-potent high-caffeine, high sugar, low polyphenol Starbucks brew as "rocket fuel" on your mission not to mars, but to your first (or next?) heart attack.

Live longer, live leaner and live diabetes-free with...coffee!

I guess, some of you will probably remember my pre-Christmas blogpost on the "Anti-Diabesity Effects of Coffee", in which I elaborated on the results of a recently published paper by Matsuda et al. who observed significant reductions in weight gain in rodents receiving either diluted coffee or pure caffeine in addition to a fattening high fat (+high carb) diet. Contrary to the body weight gain, which was ameliorated about equally effective by both treatments, the "whole coffee" treatment had a much more pronounced effect on the particularly unhealthy visceral fat in the epididymal area (cf. previous news, figure 2).

Figure 1: Molecular structure of chlorogenic and caffeic acid, two of the major phenolic compounds in coffee beans (adapted from Tsuda. 2012)

Although these results clearly indicate that there is more to coffee than the world's most popular recreational drug, caffeine, they cannot answer the question what exactly this "more" would be. The most likely candidates obviously are the two major plant phenols in coffee beans, caffeic acid and its ester, cholorogenic acid (cf. figure 1). Both, caffeic, as well as cholorogenic acid have already been studied for their antihyperglycemic (=blood glucose lowering) effects in animal models (e.g. Rodriguez de Sotillo. 2002; Bassoli 2008), but the molecular mechanism by which they perform their blood sugar reducing magic had not been fully elucidated until Satoshi Tsuda and his colleagues from the Laboratory of Sports and Exercise Medicine at the Graduate School of Human and Environmental Studies of the University of Kyoto in Japan conducted an experiment which identified the AMPK-pathway about which you have already learned so much, here at the SuppVersity, as one, if not the underlying cause of the beneficial health effects of coffee.

In view of the fact that cacao, just like coffee contains both chlorogenic and caffeic acid (Duke. 2000), it is almost certain that the health benefits which have been ascribed to the consumption of phenol rich dark chocolate within the last couple of years can be traced back to increases in skeletal muscle AMPK-phosphorylation, as well.

To prove their hypothesis that caffeic acid and / or chlorogenic acid act directly on the AMPK-pathway in skeletal muscle,  the scientists incubated isolated rat epitrochlearis muscles with different amounts of the coffee phenols and measured the phosphorylation of AMPKα Thr¹⁷² and ACC Ser⁷⁹

Figure 2: Relative AMPK-phosphorylation in isolated rat epitrochlearis muscles in response to incubation with 0.01, 0.1 and 1mM of chologenic and caffeic acid (left); relative increase in AMPK-phosophorylation after incubation with 1mM of caffeic acid for 5, 15, 30 and 60 min (right; data adapted from Tsuda. 2012)

As you can see, caffeic acid, but not chlorogenic acid lead to dose- and time-dependent increase in skeletal muscle AMPK-phosphorylation (cf. figure 2). A similar response was observedfor its downstream target (data not shown in figure 2), Acetyl-CoA carboxylase (ACC), an enzyme that is directly involved in the regulation of mitochondrial fatty acid oxidation.

Figure 3: Relative increase in AMPK isoform phosophorylation (left) and increase in glucose transport measured with 3O-methyl-glucose as a marker (right) in skeletal muscle of rats after incubation with 1mM of caffeic acid for 30 min ( data adapted from Tsuda. 2012)

And while it does not come as a surprise that the increase in AMPK went hand in hand with the previously observed increase in glucose uptake the underlying mechanisms of which the scientists tried to uncover (cf. figure 3), it is of particular importance for physical culturists and anybody else who is interested to burn fat, while maintaining / building muscle that this effect was mediated by the alpha 2, not the alpha 1 isoform of AMPK. As I hope those of you who have been following my dissertations on AMPK in the Intermittent Thought (Part 1, Part 2, Part 3) will be aware of, the former, i.e. AMPK-alpha-2 is also expressed in response to exercise and does not reduce muscle protein synthesis by compromising the mTOR response (note: due to the isoform-specificity of caffeic could be called a true exercise mimetic).

Figure 4: Relative amounts of ATP and phosphocreatine (PCr) and phosphorylated AKT in skeletal muscle after incubation with 1mM of caffeic acid for 30 min (data adapted from Tsuda. 2012)

That you do not have to be afraid of losing muscle, if you ramp up your skeletal muscle AMPK expression by caffeic acid, is also supported by the absence of any detrimental effects on skeletal muscle protein kinase B (AKT) expression and the adenosin-triphosphate (ATP) levels in the skeletal muscle samples (cf. figure 4). What is intriguing, though, is the statistically significant decrease in the amount of phosphocreatine, a phosphorylated creatine molecule your muscle (and brain) tissue uses as a rapidly mobilizable energy reserve.

Caffeic acid won't decrease protein synthesis, but could reduce the effectiveness of creatine

And while Tsuda et al. mention the detrimental effect caffeic acid exerts on intra-muscular phosphocreatine stores in the discussion of the results, they are not able fully explain this observation which reminds me of the old "myth" that the caffeine in coffee would compromise the beneficial effects of creatine supplementation... I guess we have just found why some studies did in fact support this hypothesis. If the caffeic acid induced increase in AMPK-phosphorylation goes hand in hand with a reduction in the amount of stored creatine phosphate (PCr), this could mean that you would need more creatine to achieve and maintain "maximal" levels of this high-performance energy reserve.

As you can see, it is always the same, with every question we answer a new one arises. What did Socrates say? Yeah: "I know that I know nothing!" I suppose this is a good concluding word for today's blogpost. Come back tomorrow if you want to know what else you do not know ;-)

Leucine Inhibits Nitric Oxide & Beneficial Effects of Cardio Training on Glucose Management. Plus: No Increase in Protein Synthesis W/ Protein After Eccentric Workouts?

Pre-, Post and Intra-workout supplements are a multi-million dollar business. But are the products at least half as effective as the shiny advertisements claim?

Let me guess, the actual reason you want to read this article is the shocking claim that everybody's darling, the "pro-anabolic amino acid" leucine may, in addition to having beneficial effects on the phosphorylation of mTOR and the subsequent increase in skeletal muscle protein synthesis, also have negative effects. Right? Ok, I will add a link that takes you right to my elaborations on two recent studies from the São Paulo University and the China Agricultural University and allows you to skip past the information about another recent study.

A study from the Department of Public Health at the Aarhus University and a study that raises the question, whether its results are indicate that eccentric training is potent enough to maximize the protein anabolic response to an extend that the additional provision of dietary protein will not lead to further increases in markers of protein synthesis.

You can learn more about protein intake at the SuppVersity

Protein Timing DOES Matter!

5x More Than the FDA Allows!

Protein requ. of athletes

High EAA protein for fat loss

Fast vs. slow protein

Less Fat, More Muscle!

Before we draw any conclusions, I guess we should first take a look at what Stine Klejs Rahbek and her colleagues actually did: To investigate the effects of leucine-rich whey protein hydrolysate and carbohydrate (WPH+CHO) versus isocaloric carbohydrate (CHO) supplementation on the Akt-mTOR and the AktFOXO signaling axis, during recovery from muscle-damaging exercise and to evaluate whether their hypothesis that WPH+CHO would accentuate signaling for protein synthesis and attenuate signaling for protein degradation, compared to isocaloric CHO, the researchers recruited twenty-four young healthy recreationally active men who had not participated in systematic resistance training or eccentric dominated activities for lower extremity muscles within 6 months prior to inclusion in the study.

The study itself was conducted in a double blinded, isocaloric placebo-controlled fashion in regards to dietary supplementation. Following inclusion, subjects were randomly allocated into either

• a whey protein hydrolysate+carbohydrate group (WPH+CHO, n = 12) or
• isocaloric carbohydrate placebo group (CHO, n = 12)

On the exercise trial day, subjects reported to the laboratory at 07.30 am in a fasted state. Before the eccentric exercise protocol was initiated, muscle soreness was evaluated using a visual analog scale, a blood sample was collected and knee extensor muscle contractile function was evaluated. Subsequently, a unilateral eccentric exercise protocol for was completed, lasting approximately 30 min (see below).

Figure 1: Timeline of interventions and measurements on the four study days are shown. A muscle biopsy was sampled 14 days prior to the exercise trial (i.e. to establish basal level). The protocol for days 1 and 2 was identical (Rahbeck. 2015).

Immediately after the exercise bout, the subjects ingested either a WPH+CHO or a CHO supplement, according to the group they were assigned, and then rested for 3 h. At 3-h post-exercise, a biopsy was obtained from both the exercise and the non-exercise control leg. Before leaving the laboratory, the subjects ingested the second drink (1.00 pm) and received a third drink to ingest 3 h later (4.00 pm).

"On days 1 and 2 (24 and 48 h following exercise, respectively), the subjects were instructed to ingest three supplements at absolute time points similar to day 0, with the fist drink always ingested after the functional tests and biopsy sampling. Biopsy sampling from both the ECC and the CON leg on days 1 and 2 were performed under conditions similar to the pre-exercise biopsy, i.e., the subjects fasted overnight and rested in the supine position for 45 min prior to biopsy sampling. The biopsy sampling on days 1 and 2 was timed to correspond to 24 and 48 h following exercise termination. Assessments on indices of muscle damage (muscle force, muscle soreness and plasma muscle creatine kinase) were repeated at 24, 48, 72, 96, and 168 h after overnight fasting." (Rahbeck. 2015)

All Subjects were instructed to refrain from physical activity such as exercise, stair case walking and other types of strenuous activity in the hours/ days between post-exercise assessments of indices of muscle damage to ensure that all measured effects made actually reflected the effects of the exercise + supplementation intervention.

Figure 2: Effects of eccentric training + supplementation on markers of protein anabolism (left, green) and catabolism (right, red) as measured in the trained leg (Rahbeck. 2015).

Speaking of effects: If you look at the data in Figure 2, you will realize that the eccentric training led to significant decreases in muscle force (by 23–27 % at 24 h post-exercise), which were followed by gradual, although not full recovery at 168 h post-exercise, with no differences between supplement groups. Furthermore, the phosphorylation of mTOR, p70S6K and rpS6 (=the activity of these protein anabolic proteins) increased and phosphorylation of FOXO1 and FOXO3 (=the activity of these catabolic proteins) decreased in the ECC leg, again with no differences between supplement groups.

Eccentric training impairs glucose sensitivity in healthy men (Asp. 1995).

Speaking of eccentric training, you are aware that this form of allegedly highly anabolic (this is scientifically not proven) training will induce a transient decrease in insulin sensitivity (Kirwan. 1992; Asp. 1995), right? So carb binging after an eccentric workout is probably worse than doing the same at any other time for healthy men and women with a decent baseline insulin sensitivity.

If this is not your first visit to the SuppVersity you will yet know that these observations are not sufficient to warrant the previous voiced hypothesis that the exercise induced increase in protein synthesis in response to eccentric exercises realizes as long as you are training "hard enough", because mTOR, p-p70S6K & co are no reliable measure of the actual amount of protein that's transported into the muscle after the workout.

Don't freak out about the Rahbeck study, take a look at the latest studies leucine science!

Instead of freaking out that your protein supplements may be useless, you may thus rather discard this study as interesting, but inconclusive and take a closer look at the latest evidence that leucine, when consumed in excess and isolation could have side effects you may want to avoid.

• Leucine + endurance exercise - no perfect match? In their latest study, scientist from the São Paulo University were able to show that "leucine supplementation did not potentiate the effects of endurance training on protein turnover, and it also reduced its positive effects on glucose homeostasis" (Costa Junior. 2015) - in rodents.
  
  In view of the fact that the interactions between endurance exercise, leucine supplementation and glucose metabolism have not previously been studies, the scientists analyzed the effects of endurance exercise training plus leucine supplementation on protein turnover and glucose homeostasis in healthy mice.
  

  

  Figure 3: Changes in body composition (left), changes in the expression of the catabolic ubiquitin-proteasome protiens (middle) and effects on glucose disappearance index aka effective glucose uptake after the swimming workout (right | Costa Junior. 2015).

  The results you see in Figure 3 tell you three things: (a) Leucine did not have the previously described minor minor beneficial effects on body composition (increases in lean mass are compensated by increases in fat mass); (b) it did not ameliorate the protein turnover during exercise and (c) it did actively blunt the real world increase in glucose uptake after the endurance workout in spite of the fact that changes in marker proteins like AMPK (not shown)would suggest otherwise.
  
  Reason to panic? No, the effects are not pronounced enough. In view of the fact that the benefits of isolated leucine supplementation and "spiking" other supplements with extra leucine are totally overblown, anyway. This may be the final straw that brakes the leucine guzzling camel's neck for those of you who's primary goal is to use exercise to improve their glucose tolerance.
• Leucine an "anti-pump", "anti-heart health" supplement? While they are a bit removed from human in vivo studies, the claims made by Yang et al. in their latest paper in Amino Acids are a bit frightening.
  
  Based on the observation that increased concentrations of l-leucine in the plasma occur in obese humans and other animals with vascular dysfunction, the scientists argue that the unique inhibitory effect of leucine on NO synthesis from l-arginine in endothelial cells may be part of why the increase in serum BCAA that's brought about by a failure to metabolize the branch-chained amino acids in the obese could negatively modulate cardiovascular homeostasis in insulin resistance.
  

  

  Figure 4: This is how leucine messes with NO synthesis. It increases the production of glutamine:fructose- 6-phosphate aminotransferase (GFAT) which then shuts down NO synthesis (Yang. 2015).

  "Results of recent studies indicate that l-leucine is an activator of glutamine:fructose- 6-phosphate aminotransferase (GFAT), which is the fist and a rate-controlling enzyme in the synthesis of glucosamine (an inhibitor of endothelial NO synthesis). Through stimulating the mammalian target of rapamycin signaling pathway and thus protein synthesis, l-leucine may enhance GFAT protein expression, thereby inhibiting NO synthesis in endothelial cells" (Yang. 2015).

  Yang et al. propose that reducing circulating levels of l-leucine or endothelial GFAT activity may provide a potentially novel strategy for preventing and/or treating cardiovascular disease in obese and diabetic subjects and highlight:
  

  "Such means may include dietary supplementation with either α-ketoglutarate to enhance the catabolism of l-leucine in the small intestine and other tissues or with N-ethyll-glutamine to inhibit GFAT activity in endothelial cells" (Yang. 2015).

  If the scientists (reasonable) assumptions are accurate, anything that prevents the leucine-induced activation of GFAT, be it nutritional supplements or pharmaceutical drugs, may in fact contribute to improved cardiovascular function by enhancing vascular NO synthesis. For the average trainee that's not really relevant, but if you look at the composition of contemporary N.O. boosters this revelation may explain why the "old" NO Xplode with arginine, caffeine & co worked significantly better than its BCAA-laden successors. 

Study Says "BCCAs, Don't Build Muscle!" I Say "True, But They Seem to Create an Anabolic Potential." | more

Bottom line: None of the studies presented in this research summary indicates that you have to stop taking the respective supplements. Specifically the use of protein supplements after resistance training workouts is a tried and proven way of augmenting muscle growth - irrespective of the questionably conclusions Stine Klejs Rahbek draw based solely on markers of protein synthesis and in the absence of measuring the influx of protein into the muscle after the standardized eccentric exercise protocol.

Similarly, the results Yang et al. and Costa Junior et al. present in their papers prove that the incredible hype surrounding leucine is misplaced. They do not, however, provide bullet proof evidence of side effects that are severe enough to flush your leucine and BCAA supplements down the toilette | Comment on Facebook!

References:

• Asp, Sven, Jens R. Daugaard, and Erik A. Richter. "Eccentric exercise decreases glucose transporter GLUT4 protein in human skeletal muscle." The Journal of physiology 482.Pt 3 (1995): 705-712.
• Costa Junior, et al. "Leucine supplementation does not affect protein turnover and impairs the benefiial effects of endurance training on glucose homeostasis in healthy mice." Amino Acids (2015): Ahead of Print.
• Kirwan, J. P., et al. "Eccentric exercise induces transient insulin resistance in healthy individuals." J Appl Physiol 72.6 (1992): 2197-202.
• Rahbek, Stine Klejs, et al. "No differential effects of divergent isocaloric supplements on signaling for muscle protein turnover during recovery from muscle-damaging eccentric exercise." Amino Acids (2015): 1-12.
• Yang, Ying, et al. "l-Leucine and NO-mediated cardiovascular function." Amino acids (2015): 1-13.

Fasted Cardio & Beyond - Optimal 24h Fatty Oxidation: How It Works, Why It Works & Why It Still May Not Be Worth It

Photo of a typical disciple of the cult of the "fat burning zone".

Day 3 of the SuppVersity Exercise Science Week and for some of you maybe about time to have breakfast... hold on, breakfast? But shouldn't you work out before breakfast? I mean this whole cardio in the morning business you have taken up lately is all about doing it before, not after breakfast isn't it? You grab your WIFI-connected iPhone tune in to the Super Human Radio morning cardio mash-up and hop onto your cycle ergometer, treadmill, rowing machine, elliptical, spinning bike, stepper, or whatever else you may be using  - no breakfast no intra-workout supplement - at least no carbs, right? Ah, and of course you are going to work out at the highest intensity possible, to burn more fat later on, after all, you are no disciple of the cult of the "fat burning zone", right? Right! And still you have your doubts, hah?

Now, I can't tell you whether the above has anything to do with your morning routine. What I can tell you, however, are the long and short on 24h energy expenditure by summarizing and expanding on some of the main findings of a recent paper by Kaito Iwayama and Kumpei Tokuyama, two young scientists from the Graduate School of Comprehensive Human Science at the University of Tsukuba (Iwayama. 2012). 

Let's start with the "short", then

I guess you will be familiar with the term "metabolic chamber". That's a small room, where you, as a scientists, lock your subjects up in order to monitor their energy metabolism with your fancy electronic equipment and analytical methods for a prolonged period of time (usually 24h). As Iwayama and Tokuyama point out in their latest paper this technique has long been and in fact still is considered the gold standard as far as 24h energy expenditure measurements are concerned.

"During the last 10 years, experiments with this method have raised interesting observations such as: 1) exercise intensity has no effect on 24 h fat oxidation, 2) exercise has little, if any, effect on 24 h fat oxidation, and 3) exercise before breakfast increases 24 h fat oxidation."

Just in case you are one of those guys / gals who don't read quotations, we are going to spend the major part of today's contribution to the SuppVersity Exercise Science Week recapping what "the short" is telling us about your morning, afternoon and/or evening efforts to lose body fat and extend it into "the long" by adding references an examples, so don't worry.

I. Exercise intensity has no effect on 24 h fat oxidation

If you really want to maximize fatty acid oxidation while do a HIIT session before  a lengthy steady state aerobics.You should be aware though, that we are talking about relative increases, here (read more)

We all know that the amount of energy your body consumes during physical activity will depend on the "workload", which is defined as the mathematical product of force x way. In that, the force during a lift would be gravity g x mass of your weight. For a 10kg weight, this would yield a force of 100N[ewton], let's say you lift that weight from the ground into a hight of 1m. In that case, the workload you applied would equal 100N x 1m = 100Nm. If you move a larger weight, say 20kg, for example you would have done twice as much work... it's as easy as that, but unfortunately pretty useless when it is applied to the human human body. While it may still make sense to compare "work-matched" workouts with each other, the outcome in terms of the energetic demands a "10,000Nm bodybuilding workout" will produce, is very different from that of a "10,000Nm O-lifting workout", let alone a "10,000Nm marathon run". The relation between work and energy physicists often try to explain by stating that "(mechanical) energy is a measure of the ability to do work" is too simplistic to work (all puns intended) out in exercise physiology.

If we had a phyiscal model that described what happens in your body down to the level of the individual cell, things would be different. Currently, however, we are missing 99% of that model, so that we have to find other ways to measure the exercise induced and basal energy expenditure - and this is where the metabolic chamber comes in. It allows scientists to measure the energy expenditure independent of any workload calculations and does even allow for a quantitative estimation of where that energy is coming from, namely from fats or carbohydrates (and glyconeogensis). From previous studies, which availed themselves of this amazing piece of equipment, we know already that

• for low-intensity exercise, below 40-50% of the VO2Max the energy supplied is primarily from oxidation of plasma free fatty acids
• for intensities ranging from 50% to 95% of the VO2Max, the ratio of glucose to fatty acid oxidation, the so called respiratory rate is constantly increasing; in that, a RER of 0.8 tells us that we are fuelling 80% of our energy demands from glucose, already 
• for intensities in the 100% of VO2max range, the RER approaches 1.0 meaning that our bodies satisfy almost 100% of their energetic demands by the oxidation of carbohydrates (glycogen => glucose)

This has, as we have already seen in yesterday's 2nd post in the SuppVersity Exercise Science Week, led to the commonly held belief that low-intensity exercise would be better than high-intensity exercise for increasing fat oxidation and, thus, fat loss (Hill. 1992).

The notion that what happens after your workout is about as, if not more important than the energy, let alone fatty acid expenditure during a workout has unfortunately not reached public awareness, as of yet.

That's a pitty, right? Well at least as far as the rate of fatty oxidation is concerned, I would not be too sure about that, as previous studies suggested that the amount of fat that's oxidized in the post-exercise recovery period following isocaloric exercise performed at high (65% VO2max for 1 h) or moderate intensity (45% VO2 max for 86-89 min) is identical!

"First, consistent with the literature, fat oxidation during exercise was less for high-intensity exercise than for low-intensity exercise. Second, the increase in fat oxidation during the post-exercise period seemed to be greater after high-intensity exercise, although the difference did not reach statistical significance. Third, the sum of fat oxidation during the exercise and post-exercise periods was not significantly different between the two exercise conditions of different intensity." (Iwayama. 2012)

Aside from these fundamental insights, the studies on which this rationale is based on did also provide another intriguing, yet somewhat discriminating insight:

• While women have the edge as far as intra-workout fatty acid oxidation is concerned, their ability to burn fat during rest is low compared to their male counterparts (Hanerson. 2007). According to Iwayama and Tokuyama, this biological fact may also explain why women are typically less successful in achieving their fat loss goals in response to exercise only interventions than men (Ballor. 1991; Donnelly. 2005).

Now think about this for just a second, take a look at the data in figure 1 and now tell me: "What's the best way for women to maximize fatty acid oxidation?"

Figure 1: Fatty acid oxidation in male and female subjects in the 24h period after low /40%VO2Max) and high (70% VO2Max) intensity workouts with a matched energy expenditure of 400kcal; the data was measured in a metabolic chamber by Melanson et al. ten years ago (Melanson. 2002)

Right! That's low intensity long duration workouts. Those will allow them to burn more fat (on a relative basis) during the workout without experiencing the bump in post-exercise fatty oxidation rates Melanson et al. observed in their 2002 study. And yet, neither I nor the researchers who wrote...

“Given that time is a limiting factor for most individuals, if the goal of exercise is to maximize fat oxidation to better regulate body fat mass, then exercise should be performed at the highest intensity that can be comfortably maintained.” (Melanson: 2002)

...would recommend that our female or male readers stick to "training in the zone", only. You will learn why this is the case later in the article. For the moment, I do yet want to address the second and third assertion from the initially cited three-item list, first.

II. Whether you exercise or not has no influence on 24h fatty acid expenditure

At first sight this sounds, bullocks. I mean, it should be out of question that you burn more fat, when you work out, than when you lie around on the couch, right? And in this case you are right - at least, if you include the additional fatty acid oxidation during the workout in your calculation and discard things like standard deviations and statistical non-significance.

Table 1: Independent effects of exercise intensity (low vs high intensity) and exercise itself (control vs exercise) on 24h fat oxidation have been assessed under energy-balanced study design (except for the Lausanne
study, in which subjects were in a state of negative energy balance); "no" denotes not significantly different (Iwayama. 2012)

And still, under "macronutrient-balanced condition[s"], which are a necessary prerequisite to measure the independent effect exercise has on 24-h fat oxidation without having a negative energy balance or the ingestion of some sugary intra-workout drinks skew the results towards higher, respectively lower rates of fatty acid oxidation (cf. Bielinski. 1985; Dionne. 1999).  Exactly this is what has been done in a series of metabolic chamber experiments, Iwayama and Tokuyama reference in their paper (see table 1) to support their assertion that

"fat oxidation on days with exercise doesn’t differ from sedentary control days when the energy balance is maintained." (Iwayama. 2012)

While the results are anonymous it's clear that they do not support the notion that working out would exert an independent effect on the amount of fatty acids that are "burnt" within the same 24h period the exercise bout was conducted in.

Still, as Iwayama and Tokuyama point out, "statistically not significant" does not equate non-existent. You just have to take another look at the data from the Melanson study in figure 1 to see that there is a definitive trend towards increased fatty acid oxidation in the exercise compared to the control condition.

The difference between significant findings and "unreliable" trends reminds me of a previously not mentioned, yet potentially significant disadvantage of an otherwise highly reliable method to measure the total energy expenditure of human beings: The restricted number of participants in studies using indirect calorimetry with a room-sized respiratory chamber. The "trend" in the Melanson study, for example could well have reached statistical significance with a greater number of study participants; and the same obviously goes for the rest of the studies in table 1, as well. Still, as we are going to see in the conclusion, an over-reliance on statistics is not the only reason why "not working out" is not an option. Before we tackle that, I do yet want to address the last point on our check-list.

Exercise before breakfast increases 24h fat oxidation
 
This third and last of the initially cited assertions does not only take us back to the "breakfast problem" from the introduction, it's also the only assertion that's in accordance with the mainstream understanding of the role of exercise in the process of fatty acid oxidation. "Working out on empty", "cardio in the morning" and so on and so forth - you know the whole spiel and actually you do also know the scientific explanation of why working out like this does actually work out. No idea? Well, I did provide part of the explanation in the previous paragraph, already, when I mentioned the potential impact of fasting and feasting on the experimental results.

Gluconeogenic as most of them may be, EAAs still increase GLUT-4 and thus glucose uptake by the muscle - a true yet overlooked nutrient partitioner, so to say (read more)

Did you know that the two essential L's, i.e. leucine and lysine are the only amino acids that cannot be used for glyconeogenesis by the liver? Contrary to the rest of the pack, they are exclusively ketogenic and can only be transformed into ketone bodies.

In view of the built-in glucose repartitioning effect of essential amino acids (EAA), this is yet no reason to be worried about... well, unless you are on a ketogenic diet and make the standard mistake of each and every fitness fanatic to turn a high fat diet into a high protein diet without carbohydrates, so that you end up living on the little glucose your liver is able to produce without ever getting even close to real ketosis.

I see it dawns on you: It's the sheer necessity of burning fat for fuel, in the absence of other, more readily available nutrients like carbs, or glucose the liver would generate from proteins or aminos, for example. So, in the course of your workout you are actually burning more fat than you would if you had breakfast before hopping onto the treadmill, bike or elliptical, but what about the time thereafter?

Figure 2: 24h energy expenditure and fatty acid oxidation (both in kcal/min) on days on which cardio (60min 50% VO2max light steady state) was done before (filled circles) or after (open circles); data based on an unpublished from the same group (Shimada. unpublished)

As the data in figure 2 tells you, there is no difference in the following hours and - what's even more important - the total energy expenditure was identical - 2594kcal/day vs. 2589kcal/day in the before and after breakfast trial, respectively. In addition to that, a detailed analysis of the unpublished study by Shimada et al. the above data was taken from, does also show that

• working out before breakfast reduces the energy expenditure in the time before lunch --  over the whole period the subjects burned about 500 kcal less, when exercise was performed before breakfast
• working out before breakfast burns more glycogen and increases non-oxidative carbohydrate storage during / after breakfast -- with the carbohydrate content of the breakfast being used for glycogen repletion, this does in fact lead to another increase in fatty acid oxidation, simply because the alternative fuel, namely the carbs are not oxidized, but stored

So, 2x thumbs up for cardio before breakfast - at least in the short run and when your goal is to maximize fatty acid oxidation, but ...

Is maximal fatty acid oxidation even what you should be aiming for during a workout?

I guess you will already have read between the previous lines that my answer to this question is a definitive "no". Moreover, most of you are so clever and have been following the SuppVersity posts for so long that they could come up with their own arguments against an overemphasis of intra-, post and total 24h fatty acid oxidation, when getting lean and healthy is your goal. And probably, some of them are even identical to mine:

• Firstly, and most importantly, burning fatty acids for fuel does not equate fat loss. If you follow a real ketogenic diet (not one with tons of protein in it), you'll burn (almost) exclusively fat, but even under these "extreme" conditions most of the fat will come from the fat you eat, while the small amount that's actually taken from your hips, buttocks and whatever, will be restored unless you are in a caloric deficit, when your fatty acid oxidation will increase anyways.

• 

  The "Fat Loss Support Routine" from the Step By Step to Your own Workout Routine guide would be one example of how you can structure your weekly workout regimen to cut body fat.

  Secondly, many of the metabolic benefits of exercise are closely related to the act of glycogen depletion. This is particularly true for the increase in GLUT-4 expression and consequent improvements in muscular glucose uptake, burning only fat for fuel during a workout is thus a questionable ideal.
• Thirdly, working out "in the zone" may burn the most fat but won't have the conditioning effects high(er) intensity workouts have. While obese individuals and people who have been sitting around their whole lives will see improvements in their VO2max (and in the long run their heart-health), anyone who is not totally unconditioned misses out on the structural changes in the musculature, and as you've learned on day one of the SuppVersity Exercise Science Week adipose tissue, as well.

In short, the importance of burning fat for fuel is so overrated that exercise prescriptions that are based on the paradigm of maximal fatty acid oxidation are at least suboptimal for health, fitness and physique purposes. Some people, I guess, would probably even go so far to say that they do more harm than good. I for my part leave it up do you to decide whether you join sides with my carefully worded or the more extreme version of this conclusion, or - and this would be your good right - to wholeheartedly disagree with both of them.

References:

• Ballor DL, RE Keesey. A meta-analysis of the factors affecting exercise-induced changes in body mass, fat mass and fat-free mass in males and females. Int J Obes. 191; 15: 717-726.
• Bielinski R, Schutz Y, Jéquier E. Energy metabolism during the postexercise recovery in man. Am J Clin Nutr. 1985;42: 69-82.
• Dionne I, Van Vugt S, Tremblay A. Postexercise macro-nutrient oxidation : a factor dependent on postexercise mac-ronutrient intake. Am J Clin Nutr69: 927-930.
• Donnelly JE, Smith BK. Is exercise effective for weight loss with ad libitum diet? Energy balance, compensation and gender differences. Exerc Sport Sci Rev. 2005; 33: 169-174.
• Henderson GC, Fattor JA, Horninig MA, Faghihnia N, Johnson ML, Mau TL, Luke-Zeitoun M, Brooks GA. Lipolysis and fatty acid metabolism in men and women during the postexercise recovery period. J Physiol. 2007; 584: 963-981
• Hill JO. 1992. Physical activity and energy expenditure pro-ceedings: national task force on prevention and treatment of obesity. Physical activity and obesity conference – NIDDK, pp.60-65.
• Iwayama K, Tokuyama K. Exercise in a metabolic chamber - Effects of exercise on 24 h fat oxidation. J Phys Fitness Sports Med. 2012; 1(2): 307-316.
• Melanson EL, Sharp TE, Seagle HM, Horton TJ, Do-nahoo WT, Grunwald GK, Hamilton JT, Hill JP. Effect of exercise intensity on 24-h energy expenditure and nutrient oxidation. J Appl Physiol. 2002; 92: 1045-1052 
• Shimada K, Yamamoto Y, Iwayama K, Nakamura K, Ya-maguchi S, Hibi M, Nabekura Y, Tokuyama T (unpublished observation).