Monday, January 28, 2013

How Working Out Changes the Morphology of Your Body Fat and Why This Explains that Intensity and Explosiveness Hold the Key to Getting and Staying Lean, Fit and Healthy

Can the guy on the right run away from the bloated macrophage coated fat cells on the left? Today's first post in the SuppVersity Exercise Science Week does hold the answer to this existential question.
Those of you who don't just read, but also think about the headlines of these posts will probably already have theorized about the remote possibility that I could have changed my mind and discarded the original plan to do an "exercise quickie" early this week (see SuppVersity post from Saturday). Now, before you are getting mad at me, let me give you the (as I would say good) reason for doing that: Some, if not almost all of the exercise related studies, I have piled up here are actually too interesting to end up as part of a mash-up. That's particularly true in view of the fact that my time budget during the week does not allow me to discuss them in appropriate detail. So, even if wanted to end up writing >10,000 word posts, this would only work on 48h days ;-)

The solution I came up with is easy and in my humble opinion actually quite cool: The world's first SuppVersity Exercise Science Week! In the course of the next days, I will serve you one or two of the latest studies from the realms of exercise science per day - with the rest (if there is one) being "mashed up" in the Short News on Saturday. Cool? No? Well, bad luck, then ;-)

We will kick off the week with the modulatory effect of exercise on adipose tissue

We all know that exercise is a good way to support and control diet induced weight loss. Specifically for those of us who are already on the lean(er) side of a "divide", where obese is soon going to be the new normal (see "Obese is Going About to Become the New Normal"), it's probably even obligatory, if it's not being skinny fat that's our diet goal. That being said, a recent review of Izawa et al. provides a couple of intriguing insights and links between physical activity and the structural changes our white adipose tissue is undergoing (Izawa . 2013). In this first post of the SuppVersity Exercise Science Week I am going to summarize and expand on some of these points and point towards the implications these more or less recent, in parts pretty geeky and abstract findings have on the way we could, should, or might train:
  • Training can increase lypolysis: Compared to subcutaneous fat (SAT), visceral fat (VAT) has a higher lipid turnover. Interestingly, the same high lypolytic rates which render people with high VAT so vulnerable to high levels of blood fats, are also responsible for the comparable ease with which you can shake those unhealthy VAT depots melt away, when you're working out and/or dieting. The fat around the organs is not just the easiest to store, it's also the easiest to access and liberate (Ross. 2000). That this is not a location-specific characteristic, has already been proven. What does yet still have to be elucidated, is when and due to which complex mechanisms the genetic differences between the subcutaneous and visceral fat cells are getting programmed and whether there may be a way to reverse them.
  • Training will modulate the growth environment: The maturation of stem cells into SAT, VAT, or BAT (brown adipose tissue) cells appears to be highly dependent the specific milieu in which they are in. The latter, in turn, is characterized by the presence of  various growth factors. The best known and allegedly most important ones belong to the transforming growth  factor (TGF) family. It is their presence that will control whether a stem cell turns into a "brown" = metabollically active fat cell with thermogenic abilities or a regular white one (SAT or VAT). While BMP2- and BMP-4 are responsible for the formation of white adipocytes, BMP-7 drives brown fat cell development. Together with FGF21 another of those growth factors, these proteins determine the fate of pre-adipocytes. Unfortunately, the research on the different ways by which exercise controls these factors is yet still in its infancy. We will take a closer look at what we know already in the next paragraph.
  • As you know from the "CLA Destroys Body Fat" post, PPAR-γ downregulation is also the main pathway by which conjugated linolic acid strips mice of almost all their body fat (read more). The exercise induced upregulation of the so-called hypoxia-inducible factor (HIF-1α) appears to do the exact same thing: Suppress PPAR-γ and thus hit the off switch on body fat storage.
    Training reduces WAT size and number: According to a 2004 review of the literature it appears as if exercise training (aerobic) specifically in early life reduces the number and size of WAT in rodent (Stallknecht. 2004). These results have been confirmed in a 5-week study designed that was conducted to elicit the underlying molecular mechanisms only recently (Sakurai. 2010); and the results of the Sakurai study suggest that it is one of our old acquaintances that is to "blame": The peroxisome proliferator-activated receptor-γ (PPAR-γ), a central regulator of adipogenesis! It's inhibition by physical activity is what does the trick. Now, as a diligent student of the SuppVersity you will certainly remember that this is also the main pathway by which CLA, rhein (from rhubarb) and other weight loss adjuvants work their "magic" - a blockade of the PPAR-γ receptor is like hitting the "off switch" on the body fat storage control panel. And who is it who hits that switch? Well, according to the current research it appears that this is the prerogative of the hypoxia-inducible factor (HIF-1α) which is in turn controlled by exercise induced WNT and AMPK signaling.
  • Training improves angiogenesis in WAT: While you hear about angiogenesis, i.e. the physiological process through which new blood vessels form from pre-existing vessels, oftentimes in the context of various endothelial pathologies, its induction within the white adipose tissue is actually highly desirable. Scientists have long been speculating that the insufficient wiring of the adipose organ with blood vessels and the subsequent hypoxia are at least partly to blame for the constant inflammation in the ever-expanding fat depots of the obese (Ye. 2009). Since HIF-1α (see previous paragraph) also promotes the expression of vascular endothelial growth factors and their receptors (VEGFRs / VEGFs), its downstream activation by preferably intense physical activity should improve the endothelial wiring of the fat tissue and thus help sooth the chronic inflammation, that's at the heart of many, if not all of the key-features of the "metabolic syndrome".
  • Training increases the adipocyte size depended release of adiponectin: In the past couple of months, the adipokine adiponectin turned out to do most of the good stuff (esp. improvements in glucose and fatty acid metabolism), of which scientists previously thought it was the prerogative of leptin. It is therefore important that exercise increases the rate at which a given increase in adipocyte size (obviously in response to fat storage) will increase the release of adiponectin (Miyazaki. 2010). If we use the classic notion of the adipokine as a signal the fat cells use to tell the brain and the rest of the body how much fat remains to fuel its energetic demands, you could say: Working out allows your body to see how much fat you actually got. The physiological consequences of this revelation are increases in lypolysis and fatty oxidation, as well as overall metabolic benefits.
So far for the stuff that will make you look smart, when you parrot it in front of your gymbros. In order to not just look smart, but also be smart -- and in this case train smart -- you will yet also have to know the implications of these revelations and this is exactly what the rest of this article is going to deal with:
  • Making HIIT a Hit! learn how in the SuppVersity  Special (read more) and use it to get lean & healthy and, more importantly, stay lean and healthy!
    HIF-1α <> PPAR-γ <> adipocyte crosstalk - an(-other) argument for high intensity exercise: Since the HIF-1α response to a given training stimulus decreases once the body has adapted to the stressor by increasing its exercise capacity (Lundby. 2005). The crosstalk between HIF-1α, PPAR-γ, and your fat cells provide another reason to work out in the higher range of the VO2max continuum and to never neglect the imperative of constant progression (even if it's only a progression of 0.1km/h during your sprints on the treadmill - adaptation means stagnation, if you don't raise the bar appropriately)
  • Wnt10B response to stretching - an argument for heavy eccentrics and/or statics to revamp your body (less fat, more muscle!): The findings of Akimoto et al. point towards the existence of another rather strength-training specific contributer to the fat loss and leanness promoting effects of exercise - the stretch-induced activation of the wingless-type (WNT) MMV integration site family member WNT10b, the quasi cousin of an upstream mediator of HIF-1α (Akimoto. 2005). The activation of the WTNs does actually get down to the root of the trouble and will not just inhibit the formation of new fat cells from pre-adipocytes, it will also divert the mesenchymal and not yet specialized stem cells to turn into osteroblasts (bone) or myoblasts (muscle). In fact, research has shown that WNT signaling is a major contributer to both the recruitment of new muscle progenitor cells from the aforementioned pool of yet unspecific stem cells and skeletal muscle hypertrophy (Polesskaya. 2005; Armstrong. 2005).
  • You will also benefit from integrating plyometrics into your existing routine - build the Jack of All Traits Workout
    The greater WNT response to power vs. strength training points towards the superiority of a plyometrics to get and stay lea: In view of the results of Leal et al., who report a 3x greater WNT gene response to power compared to strength training in their 2011 paper on the effect of different resistance-training regimens on the WNT-signaling pathway, plyometrics, which have way more in common with the power training protocol in the Leal study (40% lighter weights; faster, explosive contractions) than whatever powerlifting routine you may have been thinking of, should be a superior means to stay lean (Leal. 2011)
  • Exercise restores your body's fat gauge: If you wanted to pointedly summarize the exercise induced reductions in leptin expression, the associated restoration of leptin sensitivity in the obese, and the increased adiponectin release relative to the increase in fat cell diameter, you could actually say that exercise restores your body's fat gauge. It allows your brain and the other organs to see how much body fat you still got and have them react appropriately. Funnily this is also why you body will, clever as is is, pull the emergency break, whenever your body fat levels become too low (cf. "The Athlete Triad Series").
Did you know that 10% of the fat cells have to be renewed every year? I know this is speculative and we are not talking about ZERO adipocyte maturation here, but what do you think will happen when a fat cell is due and you just hit the off-switch on adipocyte maturation?
A final word of caution: I am well aware that some of you may take this article as justification for training themselves into the ground. So please(!) keep in mind that hypoxia induced WNT10 and stretch induced WNT10b signaling, as well as most of the other fancy stuff you have learned about in the previous paragraphs are stress responses that require adequate recovery periods for the metabolic and growth responses they induce to take effect. Sleep, Eat, Train, Rest, Sleep, Eat, Train, Rest, Sleep, Eat... do you notice something? Yeah, right that's a 3/1 ratio of non-stressful occupations, namely sleeping, eating and resting to a single stressor, i.e. training. In other words, 25% of your result are "made" in the gym, 75% in bed (don't make it too stressful there ;-), in the kitchen and even, when you spend time with friends and family or simply sprawl out on the couch. Think of that, when you're designing your next training routine.

References:
  • Armstrong DD, Esser KA. Wnt/beta-catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy. Am J Physiol Cell Physiol. 2005 Oct;289(4):C853-9. Epub 2005 May 11.
  • Akimoto T, Ushida T, Miyaki S, Akaogi H, Tsuchiya K, Yan Z, Williams RS, Tateishi T. Mechanical stretch inhibits myoblast-to-adipocyte differentiation through Wnt signal-ing. Biochem Biophys Res Commun. 2005; 329: 381-385
  • Izawa T, Ogasawara J, Sakurai T, Nomura S, Kizaji T, Ohno H. Recent advances in the adaptations of adipose tissue to physical activity: Morphology and adipose tissue cellularity. J Phys Fitness Sports Med. 2013:1(3): 381-387. 
  • Leal ML, Lamas L, Aoki MS, Ugrinowitsch C, Ramos MS,  Tricoli V, Moriscot AS. Effect of different resistance-training regimens on the WNT-signaling pathway. Eur J Appl  Physiol. 2011; 111: 2535-2545
  • Miyazaki S, Izawa T, Ogasawara JE, Sakurai T, Nomura S, Kizaki T, Ohno H, Komabayashi T.  Effect of exercise training on adipocyte-size-dependent expression of leptin and adiponectin. Life Sci. 2010; 86: 691-698.
  • Lundby C, Gassmann M, Pilegaard H. Regular endurance training reduces the exercise induced HIF-1alpha and HIF-2alpha mRNA expression in human skeletal muscle in normoxic conditions. Eur J Appl Physiol. 2006 Mar;96(4):363-9. Epub 2005 Nov 12.
  • Polesskaya A, Seale P, Rudnicki MA. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell. 2003 Jun 27;113(7):841-52.
  • Ross R, Dagnone D, Jones PJ, Smith H, Paddags A, Hudson R, Janssen I. Reduction in obesity and related comor-bid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med. 2000; 133: 92-103.
  • Sakurai T, Endo S, Hatano D, Ogasawara J, Kizaki T, Oh-ishi S, Izawa T, Ishida H, Ohno H. Effects of exercise training on adipogenesis of stromal-vascular fraction cells in rat epididymal white adipose tissue. Acta Physiol (Oxf). 2010; 200: 325-338.
  • Stallknecht B. 2004. Influence of physical training on adipose tissue metabolism -- with special focus on effects of insulin and epinephrine. Dan Med Bull. 2004; 51: 1-33.
  • Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes (Lond). 2009 Jan;33(1):54-66.

8 comments:

  1. Very interesting what you said "Did you know that 10% of the fat cells have to be renewed every year? I know this is speculative and we are not talking about ZERO adipocyte maturation here, but what do you think will happen when a fat cell is due and you just hit the off-switch on adipocyte maturation?"

    I think in the very long run (from 1 to 5 years), being VERY lean (everyone has his own set point, in my case I mean under 10% BF) will get you rid of many adipocytes. The less adipocytes you have, the more you get shredded and also u have less space for storing new body fat while "smart bulking". Obviously this is relevant only for bodybuilding/aesthetic purposes, I dont think it is for former obese people.

    What do you think guys?

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    1. unfortunately, I never found good evidence that this will happen (it appears logical though). If it did, however, this would be even more important for formerly obese than for BBs and figure competitors, because if you think about the increase in adiponectin in response to increases in fat cell size, you will realize that a main problem why you will have a hard time as a formerly obese keeping your weight simply because your body thinks you are hilariously lean. Why? Because you have 10x more fat cells compared to someone who was never obese and does now have the same amount of fat, so that each and every of your fat cells is only containing 10% of the amount of fat those of the "normal" individuals contain. Since the expression of adipokines is non-linear your body will think you have much less body fat than it's actually the case. What happens? Your metabolism sucks, your body feels its of prime importance you store fat, etc.

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    2. Is there anything us former fat boys can do about this? Outside of "keep on keeping on" there doesn't seem like much that can be done, which can be a little disheartening, especially when coming off a fat loss period, and watching the lower abs get covered with a layer of fat and water, despite still eating below maintaince according to the RMR calcs. My basal body temp is 0.4 - 0.7 degrees lower than I would like, I know you don't put too much weight behind BBT, but it seems to indicate that metabolism slowdown is quite significant, and perhaps, permanent?

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    3. Well, it depends on the degree of adiposity, I wrote about the issue of oxygen or rather blood supply before. If you got really fat, there is a chance... ok, let's be honest... it's almost sure that you will keep some "empty fat + skin" that you can only lose via surgical procedures, simply because your body does not really have access to it anymore.

      As far as the body temp and plateaus are concerned, there is no way you go from beer belly to sixpack abs by constant dieting. Life is cyclic and so is fat loss. Constant restriction = stagnation. I have no idea, where you are at now, but more often than not, the best way to start losing fat again is to go on a 3-4 week lean bulk, with your last energy intake as a baseline and the regular +15% increase in energy intake as a starting point.

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  2. What a fantastic post series, Professor!! Can't wait to read the next ones!! Your may want to also mention the gym-girls! We more and more of them, at least here in the UK!

    Would you mind explaining in simple layman terms whether PPAR-y: a) induces the death of fat cells (i.e. you used the term "destroy"), or b) stops them from duplicating through mitosis? Or both a and b?

    Thank you for always sharing the good science!

    Best,

    Alex

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    1. actually the cells, die anyway (sooner or later at least), this is particularly true, when they are not necessary, because they are not supplied with fat - PPAR-Gamma appears to help with both, the storage of fat, as well as the formation of new fat cells from progenitor cells. If you shut it off, the result is (in the extreme case of the rodent study) that you will deplete the fat cells you have from their contents, won't replace those of them that "die" and end up with what looks like lipodystrophy (cf. http://suppversity.blogspot.de/2012/07/cla-destroys-body-fat-increases.html)

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    2. now, obviously exercise does not totally shut off PPAR-gamma, so the effect is probably not going to be that extreme. Still, its more than just the energy expenditure and thus the lower amount of energy that is available for storage that will keep people who work out regularly lean. It's also an intrinsic anti-fat storage and adipose tissue growth effect of exercise.

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  3. Brilliant, thanks for explaining this bit - very simple to understand. I am a big fan of your posts. Will now catch up with the new ones on exercise. Thank you for keeping us educated!

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