Role of Muscle and CNS in Diet-Induced Decline of Exercise-Induced Energy Expenditure | Caffeine & Nicotine May Help!

While "calories count" when it comes to losing body fat, the notion that you would always burn the same amount of energy with a given workout - irrespective of your energy intake - is completely bogus and only one of the reasons why meticulous calorie counting won't work. 
Let's address it right away: Yes, the paper Tariq I. Almundarij et al. published in the peer-reviewed journal "Physiological Reports" (Almundarij 2017) deals with a rodent experiment, but with the goal of the study being to identify the fundamental mechanisms behind, not the extent of metabolic adaptation to calorically reduced energy intakes, this does not disqualify its results as irrelevant for humans - on the contrary (and trust me, I'd prefer a human or at least a pig study, too).

With that being said, let's take a look at what the scientists did to "investigate the role of MC4R in the modulation of muscle work efficiency, and test the hypothesis that energy restriction alters economy of activity through decreasing the response to central activation of MC4R" (Almudarij 2017).
You can find more diet related wisdom in the True or False articles at the SuppVersity

Pasta "Al Dente" = Anti-Diabetic

Vinegar & Gums for Weight Loss

Teflon Pans Will Kill You!

Yohimbine Burns Stubborn Fat

You Can Wash Pesticides Away

High Volume Diet = Success
For their study, the scientists used male Sprague-Dawley rats (total N = 48) which were selected to measure adaptive thermogenesis in a baseline population - not because Martin et al. (2010) have mad ethe argument that these animals are potentially metabolically morbid, anyway, but rather because they are metabolically morbid. Just as metabolically morbid as human beings for whom the ever-increasing obesity rates indicate that we are similarly susceptible to diet-induced obesity and the associated detrimental health effects.

These rats were subjected to 3 weeks of 50% calorie restriction (CR). Over the course of this - in rodent years - intermediate time period, the scientists assessed their lab animals resting and nonresting energy expenditure (EE) and calculated the total, as well as the activity-associated EE, muscle thermogenesis, and sympathetic outflow.
Figure 1: Three weeks of 50% calorie restriction (CR) significantly suppressed both resting and nonresting EE, including physical activity-related EE, i.e. the energy you spend while working out (Almundarij 2017).
You can see the results of this basic measurement in Figure 1: The prolonged food restriction resulted in a 42% reduction in daily energy expenditure, a 40% decrease in resting energy expenditure, and a 48% decline in nonresting energy expenditure.

Dieting is when you leave only 360kcal not 600kcal in the gym, despite doing the same workout

What is particularly interesting, yet often forgotten when we talk about dieting (especially within the fitness community), is the fact that the energy that you will burn during exercise will also decrease significantly (see Figure 1G). One of the implications of the study at hand we cannot ignore is that the reduced physical activity energy expenditure stems from "the dampening of both the amount and energetic cost of activity" (Almundarij 2017) - and the latter, i.e. the reduced energy expenditure in response to a standardized exercise regimen amounts to a 30-40% decrease in EE that would degrade the 600kcal you believe to be burning on the treadmill to a meager 360-420 kcal/session!
Figure 2: Fat & lean mass and the rel. (%) difference in body comp. w/ ad-libitum vs. restricted diet (Almundarij 2017).
This 180-240kcal difference, alone, could easily explain why you see people complaining all over the internet that "[they] don't lose weight, even though [they're] doing everything right, not missing any of their daily workouts and not cheating on [their] diets" (modeled on the often-heard complaint of dieters worldwide).
Illustration of the allegedly over-simplified example calculation to show the significance of the fasting-induced reduction in AIEE for meal timing and fat loss as observed in Garaulet 2013.
Never forget the importance of reductions in activity-induced energy expenditure: You may remember an older study that has recently resurfaced on Facebook from previous SuppVersity articles about fasting: The study, "Timing of food intake predicts weight loss effectiveness" (Garaulet. 2013), indicates that having your major meals in the AM when dieting favors fat loss even if the total energy intake is identical. Knowing how significant the reduction in activity-induced energy expenditure (AIEE) in man is (%-age wise its contribution to the metabolic downregulation is much higher in man vs. rodent), the results of the study at hand may easily explain why CICO (=the C-alories I-n vs. C-alories O-out hypothesis) failed in Garaulet's study.

Let's illustrate that with a simple example (see Figure to the left). Let's assume the reduction in AIEE is indeed 40%. Let's further assume that you'd "burn" ~1000kcal from working out and walking in your waking phase before the PM meal and only 150kcal after the PM meal when eating an energetically balanced. According to Cooker, that would put your effective AIEE while dieting to 600kcal + 150kcal when you eat in the PM, but 1000kcal + 90kcal if you eat the meal in the AM. Obviously, this oversimplified example assumes that the metabolism would not slow down over the day (which will be the case). Eventually, the difference will thus certainly be smaller (maybe 15% instead of the 31% in my example). That does not mean, though, that it could not still be statistically and practically significant (note: it is unlikely that a relevant reduction would be observed for intermittent fasting in the absence of a significant caloric deficit).
In this context, it is also important to emphasize that these decreases in EE were significant even when the reductions in body weight and lean mass were taken into account. In other words, it is not the often-cited loss of lean mass (alone) which mediates the reduction in basal and exercise-induced energy expenditure. This alone, however, is nothing we didn't observe in previous human studies, already. What's truly new, however, is that the study at provides extended mechanistic insight into the origin of these unwanted reductions in energy expenditure. In fact, the study at hand ...
is the first report of reduced muscle NETO [norepinephrine turnover], indicating lower SNS drive to skeletal muscle after 3 weeks of food restriction (Fig. 2), an effect not seen during short-term energy restriction (Dulloo et al. 1988)" (Almundarij 2017).
With the importance of skeletal muscle to both resting and activity EE, (Zurlo et al. 1990; Gallagher et al. 1998), "this low SNS drive" could, as the authors further point out significantly "contribute to both the resting and nonresting aspects of adaptive thermogenesis" (Almundarij 2017).
Figure 3: The MC4R induced increase in energy expenditure in the study at hand is probably not coincidentally of a similar magnitude as the effects of nicotine (Almundarij 2017).
Nicotine targets the mechanism even more directly than caffeine: Even though the safety of nicotine as a fat loss adjuvant is, as previously discussed in detail, debatable, I think it's worth mentioning that Mineur et al. have shown 6 years ago that nicotine's effect on food intake are mediated by an activation of POMC neurons, neurons that will then activate the very melanocortin 4 receptors of which the study at hand shows that their medical activation can - albeit only partly - restore the reduced energy expenditure in dieting rats (as you can see in Figure 3, the MC4R agonist will, just as it has been shown for nicotine in humans, also increase the energy expenditure in non-dieting rats.
The latter, i.e. the ability of the muscle mass to react to central nervous system stimuli, however, is not lost while you're dieting. It is - and that's a primary result of the study at hand - rather centrally (in the brain) deactivated. Otherwise, the muscles wouldn't have reacted to either the central MC4R agonist nor any form of physical activity with an increase in thermogenesis. This result is of paramount importance, because it does, as the authors point out, ...
"[...] provide potential avenues to counter adaptive thermogenesis and [thus to] promote continued weight loss and weight maintenance through targeting physical activity EE and skeletal muscle thermogenesis (Almundarij 2017).
Now the bad news is that the melanocortin 4 receptor agonists Almundarij et al. used in their study are not (yet?) ready to be used in human beings. Other tools to increase the decreased norepinephrine turnover in skeletal muscle, however, are available and you'll all be familiar with their names: caffeine or ephedrine (and to a lesser extent green tea extract).
Figure 4: Effects of caffeine (CAF) and ephedrine (EPH) alone or in combination (C+E) on epinephrine levels during exercise. 12 recreational runners (10 males and 2 females; 6 regular coffee drinkers and 6 irregular or non-caffeine users) ingested placebo (PL), CAF 4 mg/kg, EPH 0.8 mg/kg or C+E (CAF 4 mg/kg and EPH 0.8 mg/kg). After 90 minutes of rest they performed a 10km run while wearing a helmet and backpack weighing 11kg; the intensity of this effort was >90% of VO2peak; * p < 0.05 vs PL; † p < 0.05 vs EPH; ‡ p < 0.05 vs CAF; § p < 0.05 vs C+E (Magkos 2004)
As Magkos et al. pointed out in their 2004 paper in Sports Medicine, "[b]oth drugs may enhance norepinephrine turnover, but each one alone only modestly". This supposition is supported by both previous human data (Berkowitz 1970), as well as data presented in the researchers own paper which shows that the benefit of combining the two is mostly due to the prolongation and potentiation of caffeine's effect by ephedrine (or vice versa; cf. Dulloo 1992).

Figure 5: There is a link for nicotine and there may even be a link of caffeine to the melanocortin 4 receptor - one that's mediated by the POMC neurons.
Unfortunately, corresponding data on caffeine's muscle-specific norepinephrine turnover is (and I openly admit that) not yet available. That's mostly because research has not really zoned in on the autonomic modulation of muscle compared to adipose tissue; and where it did, this was not about the effect of caffeine and co., but the upstream effects of melanocortin receptor activity (Gavini 2014), which would yet be a downstream target of the caffeine, if Laurent et al. are right and "caffeine ingestion promotes corticotropin-releasing factor release from the hypothalamus [...], which, in turn, increases POMC release" and - guess what - downstream melanocortin 4 receptor activity.

In a different context this relationship has already been established (Bhorkar 2014), whether and to which extent caffeine stimulates the melanocortin 4 receptors (MC4R), however, is - at least as far as I know - not known. Anyway... when all is said and done, there's still no doubt that caffeine, even when it's used alone, will still have a significant enough effect on the sympathetic nervous system (SNS) to promote weight loss and weight maintenance in multiple diet studies (Dulloo 1989; Westerterp‐Plantenga 2005) - and let's be honest: many people won't even care if that involves an increase in MC4R activity or not ;-)
If your diet of choice is a ketogenic diet, caffeine will not just help you to compensate the reduction in exercise-induced energy expenditure and thus "restore the calories" you leave in the gym. A recent study shows that it will also help you to get and stay in ketosis - and that's even when you've been cheating on carbs | learn more.
So what's the implication for human beings? Even though a reduction in thermogenesis at rest contributes less to the reduction in energy expenditure during periods of restricted dietary intake in humans compared to rodents. The effect of on non-resting EE and thus regular activity- and exercise-induced EE is proportionally even higher - and increases the more weight you lose (Leibel  1995).

Now, this effect reflects in a reduced central activation of hypothalamic melanocortin receptors, which could be countered by medical intervention only theoretically. After all, corresponding drugs as they have been used for experimental purposes on the rodents in the study at hand are still in the early experimental phase - that they do work without short-term side-effects has yet been demonstrated in obese individuals by Chen et al. (2015) who observed a 111 kcal/24 h increase in REE.

For the average gymrat, these drugs will yet probably never be available legally. Against that background you can count yourselves lucky that Almundarij et al.'s results also point to another, already available and (if used sensibly) perfectly safe class of drugs. central nervous stimulants like the ubiquitous caffeine. These agents have a proven record of being able to promote diet-induced fat loss by increasing/restoring SNS-induced thermogenesis (Dulloo 1988 & 1989) - especially when used in conjunction with exercise so that they can partly compensate the diet-induced reduction in sympathetic tone and thus restore the significantly reduced energy expenditure during workouts to near-normal levels.

It is often belittled, but even in non-dieting humans, the increase in energy expenditure following the consumption of caffeine is significant (Astrup 1990).
In conjunction with caffeine's ability to shift the fuel oxidation from glucose to fatty acids and its likewise central nervous system-mediated lipolytic (=fat releasing) effect on fat cells, it is thus still the most widely available and best-researched diet aid - an aid that doesn't make dieting obsolete, but one that will partly compensate the negative effect of prolonged energy restriction on basal and exercise-induced thermogenesis. Ah, ... and let's not forget that nicotine is a viable yet, as previously discussed, less harmless OTC alternative of which we know already that it acts via the same downstream signaling cascade as a melanocortin receptor agonist (Mineur 2011) | Comment!
  • Almundarij, Tariq I., Chaitanya K. Gavini, and Colleen M. Novak. "Suppressed sympathetic outflow to skeletal muscle, muscle thermogenesis, and activity energy expenditure with calorie restriction." Physiological Reports 5.4 (2017): e13171.
  • Astrup, A., et al. "Caffeine: a double-blind, placebo-controlled study of its thermogenic, metabolic, and cardiovascular effects in healthy volunteers." The American journal of clinical nutrition 51.5 (1990): 759-767.
  • Berkowitz, Barry A., James H. Tarver, and Sydney Spector. "Release of norepinephrine in the central nervous system by theophylline and caffeine." European journal of pharmacology 10.1 (1970): 64-71.
  • Bhorkar, Amita A., et al. "Involvement of the central melanocortin system in the effects of caffeine on anxiety-like behavior in mice." Life sciences 95.2 (2014): 72-80.
  • Bracco, David, et al. "Effects of caffeine on energy metabolism, heart rate, and methylxanthine metabolism in lean and obese women." American Journal of Physiology-Endocrinology and Metabolism 269.4 (1995): E671-E678.
  • Chen, Kong Y., et al. "RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals." The Journal of Clinical Endocrinology & Metabolism 100.4 (2015): 1639-1645.
  • Dulloo, A. G. "Stimulation of thermogenesis in the treatment of obesity: A rational approach." Journal of obesity and weight regulation (USA) (1988).
  • Dulloo, A. G., et al. "Normal caffeine consumption: influence on thermogenesis and daily energy expenditure in lean and postobese human volunteers." The American journal of clinical nutrition 49.1 (1989): 44-50.
  • Gavini, Chaitanya K., et al. "Leanness and heightened nonresting energy expenditure: role of skeletal muscle activity thermogenesis." American Journal of Physiology-Endocrinology and Metabolism 306.6 (2014): E635-E647.
  • Garaulet, Marta, et al. "Timing of food intake predicts weight loss effectiveness." International journal of obesity 37.4 (2013): 604-611.
  • Laurent, Didier, et al. "Effects of caffeine on muscle glycogen utilization and the neuroendocrine axis during exercise 1." The Journal of Clinical Endocrinology & Metabolism 85.6 (2000): 2170-2175.
  • Leibel, Rudolph L., Michael Rosenbaum, and Jules Hirsch. "Changes in energy expenditure resulting from altered body weight." New England Journal of Medicine 332.10 (1995): 621-628.
  • Magkos, Faidon, and Stavros A. Kavouras. "Caffeine and ephedrine." Sports Medicine 34.13 (2004): 871-889.
  • Mineur, Y. S., Abizaid, A., Rao, Y., Salas, R., DiLeone, R. J., G√ľndisch, D., ... & Picciotto, M. R. (2011). Nicotine decreases food intake through activation of POMC neurons. Science, 332(6035), 1330-1332.
  • Mountjoy, Kathleen G. "Functions for pro-opiomelanocortin-derived peptides in obesity and diabetes." Biochemical Journal 428.3 (2010): 305-324.
  • Westerterp‐Plantenga, Margriet S., Manuela PGM Lejeune, and Eva MR Kovacs. "Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation." Obesity 13.7 (2005): 1195-1204.
Disclaimer:The information provided on this website is for informational purposes only. It is by no means intended as professional medical advice. Do not use any of the agents or freely available dietary supplements mentioned on this website without further consultation with your medical practitioner.