Burn Fat and Improve Endurance by 70%. Now in Pill Form.

What if I told you there was a way to increase your endurance by 70%?  People would be lining up and asking if we have it in pill form, and we almost do.  Most people are familiar with the idea of “hitting the wall”.  That moment when you are doing some sort of endurFance based activity and you just reach a point where you can’t go on.  Maybe your thinking gets cloudy.  Your muscles don’t seem to work anymore.  Your coordination has suddenly evaporated.  That image of the Ironman triathlete, just yards away from the finish line stumbling around.  So close to the end but unable to even coordinate those last few steps to get across the finish line.

Generally this is the effect of not having enough glucose in the blood stream to supply the brain with sufficient amounts to meet its energy demands.  No matter how badly you want to go, when blood glucose drops too low the brain just says no.  Like an automobile engine running out of gas.  So the longer you can maintain a higher blood glucose level, the longer you can go before hitting that proverbial wall.

Normally regular endurance exercise has three primary affects that spare blood glucose.  1) The transformation of muscle fibers to types with more oxidative capacity, which equals more energy production out of every gram of glucose used as fuel.  2) An increase in the number and activity of mitochondria, the powerhouses of cells where aerobic metabolism occurs. 3) The improved utilization of fatty acid as a fuel source, sparing the use of blood glucose and our stored carbohydrates in the form of liver and muscle glycogen.  Who doesn’t want to use more fat as fuel source.

Of course these changes take a great deal of hard work over a prolonged period of time.  As any new runner or average person struggling to lose body fat will tell you, change is difficult, comes slowly and is often hard to notice at all.

Well thanks to a nifty little molecule called peroxisome proliferator-activated receptor delta (PPARδ) we may be able to hack into our normal metabolic processes and accelerate our fat burning capabilities.  For the performance athlete this means sparing precious blood glucose and carbohydrate stores which will push the proverbial wall out further, enabling significantly longer, and greater achievements.  For the rest of the population the implications are just as significant.  Individuals dealing with obesity and other metabolic diseases may have a tool that helps them manage their conditions and make major improvements in their health.

PPARδ is what is known as a nuclear receptor and under normal circumstances it helps kick off the process of the transformation of muscle fibers to more oxidative types along with increasing the use of fatty acids as a fuel source in skeletal muscle.  It increases this switch to using fat as fuel through its interaction with two mitochondrial proteins, Cpt1b and Pdk4.  Carnitine palmitoyl-transferase 1b (Cpt1b) is an enzyme that limits the rate at which fatty acids are transported into mitochondria.  If you enable more fatty acid to enter, you are able to use more of it as fuel.  Pyruvate dehydrogenase kinase isozyme 4 (Pdk4) is involved in regulating the use of pyruvate.  Pyruvate is a byproduct of the metabolism of carbohydrates and it is then used in another metabolic pathway known as the citric acid cycle (also known as the TCA cycle or Krebs cycle) to produce even more energy.  You don’t need to be a molecular biologist to realize that impacting these two gatekeeper molecules can have a major effect on metabolism.  And now we know that PPARδ seems to be the key to impacting these two key proteins.

In experiments in which mice are manipulated to have more PPARδ, the mice are able to run twice as long as control subjects (Wang et at., 2004).  When the mice are manipulated to not have PPARδ they have problems with the generation of mitochondria and the determination of muscle fiber type (Schuler et al., 2006).  If a drug is introduced that activates PPARδ a cascade of positive metabolic and performance benefits are seen.

PPARδ stimulation increases fatty acid metabolism and improves performance

A recent study by Fan et al. (2017) took a closer look at the role of PPARδ and how its manipulation can impact metabolism and performance.  This study was conducted in mice but keep in mind we use mice for early experiments because their physiology is very close to humans and the results we see serve as successful stepping stones to studies and interventions in humans.  And yes, PPARδ is found and active in humans.

When the authors compared normal mice to ones without PPARδ they found the normal mice showed changes in fuel use from glucose to fatty acid after 4 weeks of running while the mice without PPARδ did not show these same metabolic shifts.  Metabolic activity related to the genes impacted by the two gatekeeper proteins, Cpt1b and Pdk4, which are affected by PPARδ were either reduced by 50% or completely absent.  Performance wise, the mice missing PPARδ were only able to run half as long as the normal mice.  While the shift to fat burning occurred, the mice without PPARδ who ran still saw a change in muscle fiber type and an increase in mitochondria.  Clearly it was the fuel source metabolic change that accounted for the increase in performance.

When the authors treated the mice with a drug that activates PPARδ for 8 weeks they found metabolic changes that indicate a significant shift towards increased fatty acid metabolism.  There was a strong increase in the expression of the two mitochondrial gatekeeper genes Cpt1b and Pdk4 and a decrease in anaerobic glycolysis (carbohydrate fueled metabolism).  When the drug was given to the mine manipulated to not have PPARδ none of the changes that are normally expected occurred indicating that all the metabolic and physiological changes we are concerned with are dependent on muscle PPARδ.  Performance wise, the mice given the PPARδ stimulating drug were able to run for 1.5 hours longer then the mice without it.

Increased endurance via blood glucose sparing

The authors theorized that the reason for the increased performance in the drug treated mice was that the increased fatty acid metabolism stimulated via PPARδ spared blood glucose levels.  Both drug treated and non-drug treated mice stop running and often pass out once they hit a blood glucose level below 70 mg/dL.  In control mice blood glucose levels begin to drop between 90-120 min.  In the drug treated mice, blood glucose levels were able to be maintained for extended periods of time and often did not even begin to drop until after 180 minutes.  These types of glucose sparing improvements are the same that are seen with exercise training.  This switch from glucose to fat fueled metabolism maintains blood glucose levels high enough to continue supporting the needs of the brain and other tissues allowing for the significant increases in performance.

In addition to all of this there was also an up-regulation of 492 genes and a down-regulation of 483 genes within the quadriceps of the tested mice.  These included genes that have roles in carbohydrate and fat metabolisms and insulin activity.

So there you have it.  PPARδ turns out to be the main regulator of changes in energy substrate use in muscles.  Increase its activation and you stimulate muscle cells to use more fat based energy sources, sparing blood glucose and extending performance.  The first question you should be asking now is can we take the drug that was used in this study and achieve the same results in humans.  The version used in mice is unfortunately not safe for humans however a company has already been set up and is in the process of developing a version that is safe for human consumption.  While how to address drugs like this in competitive sport performance is an entirely different problem there is no question it could have significant impacts on a range of metabolically related diseases.  So while you are waiting for your PPARδ stimulator in pill form, get out and do some endurance work and stimulate some fat burning/glucose sparing metabolic changes along with enhancing oxidative capacity of muscle fibers and stimulating the growth of additional mitochondria the old fashioned way, by breaking a sweat and doing some work.

Works Cited:

Fan, W., Waizenegger, W., Lin, C.S., Sorrentino, V., He, M., Wall, C., Li, H., Liddle, C., Yu, R., Atkins, A., Auwerx, J., Downes, M., and Evans, R. (2017) PPARδ Promotes Running Endurance by Preserving Glucose. Cell Metabolism 25, 1186-1192

 Schuler, M., Ali, F., Chambon, C., Duteil, D., Bornet, J.M., Tardivel, A., Desvergne, B., Wahli, W., Chambon, P., and Metzger, D. (2006). PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fiber-type switch, obesity, and type 2 diabetes. Cell Betab. 4, 407-414.

Wang, Y.X., Zhang, C.L., Yu, R.T., Cho, H.K., Nelson, M.C., Bayuga-Ocampo, C.R., Ham, J., Kang, H., and Evans, R.M. (2004) Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol. 2, e294.

Exercise improves cognitive function in adults over 50. Break a sweat and build your brain.

Over the past few years we have all heard of one study or another that says exercise is good for your brain function.  Well now there is a new meta-analysis that adds to the evidence that exercise improves cognitive function for adults older than 50.  So whether you are training older adults, are over 50 yourself, worried about getting older or just looking for material to email to your parents to harass them into exercising now you have the evidence to guilt them or yourself into getting off the sofa and breaking a sweat.

For those of you who aren’t research geeks like me, a quick primer on what a meta-analysis is.  It is a type of study that takes the results for a number of different studies and combines their results to form a single conclusion that has more statistical power then the individual studies.  An individual study might only look at a few particular variables regarding the issue at hand.  It may have a limited population of subjects and be prone to certain types of errors or biases.  Often different studies on the same topic will come up with different results and conclusions creating a situation where you don’t know which studies are correct and should be followed.  A meta-analysis tries to overcome these limitations by compiling multiple studies, often with differing results, and analyses them in a way that balances out these differences resulting in a final conclusion that accounts for all of the evidence available.  It is still limited by the information in the studies it complies but for the primary question at hand, it generally offers a more complete conclusion.

In this particular study the authors looked at the effects of different forms of exercise including aerobic, resistance, a combination of both, tai chi and yoga on cognitive function.  They also addressed the affect of different training variables including duration, frequency, intensity and length of the exercise session.  Ultimately they were interested in determining the impact of all of these different factors on global cognition as well as the specific areas of attention (sustained alertness, the ability to process information rapidly), executive function (cognitive processes responsible for the initiation and monitoring of goal-oriented behaviors), memory (storage and retrieval of information) and working memory (short –term manipulations of encountered information).

The analysis was limited to studies where the exercise programs were actually supervised and lasted at least 4 weeks.  This allows for some measure of assurance that the subjects actually did the prescribed exercise as intended and for a long enough period of time for the exercise to have a measurable effect.  Studies with subjects of differing cognitive abilities were included though samples with subjects who had other neurological conditions such as strokes or mental illness such as depression were not included.  Ultimately 36 studies were included in the final quantitative analysis.

As for the good news, aerobic exercise, resistance training, a combination of the two and tai chi all were found to have a positive effect and improved cognitive function in adults over 50.  The effect was seen regardless of the cognitive status of the participants.  A particularly pronounced effect from resistance training was seen for executive function, memory and working memory.  The results for Tai chi were very promising but the number of studies that focused on that intervention were small so further research in the area is needed but the initial suggestion is that it could be a very powerful intervention, especially useful for those individuals who cannot perform more traditional aerobic and resistance training due to physical limitations.

When it comes to time, moderate length exercise sessions of 45-60 minutes were far and away the most beneficial.  This doesn’t mean shorter or longer sessions are not good for your brain, just that the results of this study show the most improvements overall working in that moderate range.

Both moderate and vigorous intensity were found to have similar positive impacts while low intensity exercise did not have a statistically significant impact.  This tends to go along with the results we have been seeing in much of the HIIT research we have been talking about recently.  When individuals have the capacity to go harder, the results seem to be greater though when looking at overall populations, the impact of moderate intensity appears to have overall similar effects.  Considering the psychology of most people, being able to achieve such positive benefits with moderate effort means we can reach that huge segment of people in the middle who are willing to exercise but not push themselves to that vigorous level.  While the low intensity work did not reach a level of statistical significance, the trend was still positive and it is far too early to say that exercise at a low intensity doesn’t have a cognitive effect.

All weekly frequencies of exercise as well as the overall length of time of the intervention showed significant impacts.

There you have it, aerobic and resistance training done for 45-60 minutes on as many days of the week as possible at a moderate to vigorous level of intensity improves your brain function.  Now you just need to remember to get up and do it and have the drive and commitment to focusing on your goal and following through with it.  If only there was something you could do that would improve your memory and executive function.

Works cited:

Northey, J., Cherbuin, N., Pumpa, K., Smee, J. and Rattray, B. (2017) Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis.  Br J Sports Med. April 24