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

While "calorie 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).
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).
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).
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 ;-)
References:

• 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., Gündisch, 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.