Written by Daniel Gwartney, M.D.
02 June 2018

17NN340-protein

Fat Loss Breakthrough

Manipulating Protein Intake To Get Really Lean

 

 

Protein and weight loss— it is driving me insane.

There is the easy and basic— protein is an essential macronutrient component of the diet, consisting of amino acids. You eat too little protein, and your body robs your skeletal muscle to provide essential amino acids and ketones to support vital organs (e.g., heart, brain and liver).1 People following hypocaloric diets (eating fewer calories than they burn to lose weight) are better able to adhere to their diet plan, satisfy their hunger more quickly and maintain their basal metabolic rate (i.e., energy expenditure or how many calories you burn at rest) as well as lean mass (e.g., muscle) IF they consume a greater amount of protein.2

 

Great! For the kind of person who doesn’t read the instructions before putting together something more complicated than a peanut butter and jelly sandwich, this is enough information. Yet, the public still struggles with weight loss. Dieting often becomes intolerable as primitive pathways are activated, leading to foraging and unplanned feeding behavior. Extremes in dieting and fat loss can lead to eating disorders that might reflect physiologic need rather than a psychological pathology.3 It is not uncommon for wrestlers to fail to “make weight,” or bodybuilders to fail to achieve a shredded appearance onstage because they couldn’t control binge eating.4

 

For the typical person, meaning not an athlete or bodybuilder, increasing the intake of dietary protein can improve both adherence (i.e., sticking to a diet plan) and efficacy (i.e., how well it works) through the routes mentioned above.5 Traditionally, dieters followed low-fat plans that provided the majority of calories from carbohydrates. The relatively low percentage (~15%) and total amount of protein consumed daily (~60-70 grams) may be sensed by the body as a crisis state, and pathways in the brain are turned on or off— resulting in cravings, hunger and difficulty reaching satiation (fullness) after a meal. This leads to increased food seeking, and often the selection of protein-rich foods— of course, these often have high fat content as well. As always, this is more easily seen in rats, as they don’t have a freezer full of Ben & Jerry’s ice cream or a drive-through Dunkin’ Donuts nearby.

 

Bodybuilders and athletes generally consume sufficient, even excess protein, in the non-stressed state. Based upon consultation requests from trainers and coaching staff, female athletes and those in weight-restricted sports appear to be more vulnerable to drastic weight-loss diets or unsound advice.3,4 For the bodybuilder, the pre-contest period is a particularly trying time, as every unnecessary calorie is stripped from the diet to maximize fat loss and prevent water retention. Additional training, posing and cardio increase the physical stress; additionally, sleep disruption as well as contest-related anxiety can further promote a negative metabolic and mental state. So, what would usually be enough is, well, not enough.

 

Protein Quality Matters

It is not just a matter of protein quantity, but it’s the quality of protein that matters. Most readers are familiar with whey protein, as it has shown itself to be the king of (single-source) protein when it comes to building muscle. The reason whey is so highly regarded lies in its amino acid profile. Whey is very high in the branched-chain amino acids (BCAAs) leucine, isoleucine and valine. These three BCAAs comprise a very high percentage of contractile protein in muscle. In other words, the stuff in muscle that lets you push and pull. Just like a rope-tugging chew toy that your dog plays with, the actin and myosin chains that form contractile proteins “wear and fray” with exercise. Eventually, they would break, but the body has repair mechanisms that allow for damaged actin and myosin chains to be restored and even strengthened— the goal of weight training, if there are sufficient building blocks (amino acids) available for repairing and hypertrophy. Unused, muscles atrophy as the body seeks to rid itself of the unnecessary metabolic burden of dormant tissue, redistributing the essential nutrients elsewhere.

 

Though much of the attention on amino acids focuses on BCAAs, and especially leucine (for good reason), that does not dilute the need for the remaining “essential amino acids” (EAAs). There are nine amino acids that the body is unable to create; the 12 non-essential amino acids can be formed in the body using other amino acids as the contributing backbone, changing side chains on the molecule to create other amino acids needed to produce the multitude of proteins in the body. The other six EAAs (besides leucine, isoleucine and valine) are histidine, lysine, methionine, phenylalanine, threonine and tryptophan.

 

Whey is less effective at providing sufficient amounts of other EAAs, particularly phenylalanine and tryptophan. In part, this is due to the relatively low concentration of these two amino acids in whey. However, another factor that needs to be considered is that the rapid influx of BCAAs compete with phenylalanine and tryptophan at the level of specific transporters that carry this class of amino acids (large neutral amino acids, or LNAAs) from the gut to the circulation, and from the circulation into tissues such as muscle or the brain. It has been shown in animal studies that consuming a protein with a high concentration of BCAAs lowers the amount of tryptophan that enters the brain’s circulation, reducing the production of serotonin (a neurotransmitter).6

 

There is a need for other proteins, particularly those high in histidine and tryptophan, even for those who supplement the diet with copious amounts of whey protein. In fact, there is no single perfect protein, as many factors determine the value of each protein. Slowly digested proteins, such as casein, may offer advantages prior to periods of fasting (e.g., overnight sleep) or prior to prolonged exercise; fish protein is high in taurine and glycine, and appears to support weight loss and fat burning; egg protein is high in methionine and phenylalanine, and has a strong appetite-suppressing effect.7,8

 

So, it should come as little surprise that the body not only monitors the quantity of protein is in the diet, but also the quality— how well it provides all EAAs. In fact, rodent studies show these animals will avoid food pellets created to be deficient in one or more essential amino acids, selecting instead otherwise identical pellets that are complete in their amino acid profile.9 If a poor-quality protein is all that is available, overeating occurs to compensate for the deficient amino acid until the body’s needs are met. This may result in extreme overeating and pathologic weight gain. It is not dissimilar from a condition known as pica, which occurs in populations where the food is iron deficient. Natives to these areas will resort to eating dirt, as the body drives for more food to meet the needs of that one micronutrient (iron).10 Pica can also be a manifestation of a psychological disorder, and has responded to serotonin reuptake inhibitors, suggesting a potential role in tryptophan uptake or metabolism.11

 

How the Body Monitors Protein Intake

To allay any concerns about “dirt binging” if whey protein is back-ordered, the human body is remarkably resilient when it comes to protein intake. In fact, it takes some time for a deficiency state to manifest relative to amino acids, due to a huge storage pool called skeletal muscle. However, as you may deduce, if the body needs to rob the muscle for amino acids, it is doing so by catabolizing the very same muscle that required months to years of dedicated training to build to its current state. Therefore, it is worthwhile giving some thought to what proteins are consumed throughout the day, to avoid some whey-dependent imbalance.

 

So, how does the body monitor protein quantity and quality intake? An excellent review recently addressed these points.12 Three different pathways are considered viable possibilities: amino acids interact directly with receptors in the brain; the “gut” (i.e., intestines and liver) senses amino acids and generates neural signals and hormonal messengers; and/or a nutrient-specific hormone is released.12 One or all of these pathways may affect behavior/metabolism/appetite in a manner that supports weight loss/fat loss.

 

In the brain, there is an enzyme that is turned on when either a non-specific amino acid deficiency is sensed (any of the essential amino acids), called GCN2; or another that is specific to leucine, that directly suppresses the appetite by altering the balance of two competing pathways in cellular metabolism (mTOR vs. AMPK).13,14 The leucine effects are not duplicated by other amino acids, suggesting this amino acid (high in whey) is uniquely viewed as a signal of the nutritional environment. Thus, dairy-based proteins used in weight-control shakes can be practical tools for the consumer seeking to lose weight and avoid later hunger or binge eating.

 

The brain does indeed regulate most behavior, but the “sensing” is often done peripherally, meaning in other tissues. It has been shown that a low leucine or BCAA diet does not induce hyperphagia (overeating), and that directly infusing (injecting) amino acids did not block the overeating effect induced by a low-protein diet. This strongly suggests that something senses the quantity and quality of protein as it is being consumed, affecting feeding behavior more strongly than what the brain senses from its blood supply.14 Further, supplementing BCAA in protein-deficient rat chow did not keep rats from selecting a lower BCAA chow that had adequate and complete protein.15

 

There are taste receptors on the tongue that detect amino acids; additionally the intestines, as well as the liver, produce vagal signals that generate a distinct pattern in the brain in areas involved with appetite.16-18 Further, hormones generated during digestion also impact feeding to signal satiation (fullness).19

 

Stimulating the “Browning” of White Fat

The final pathway is exciting due to its novelty and potential. FGF21 (aka fibroblast growth factor 21) is a metabolic hormone that has been shown to reduce blood sugar, improve the lipid profile (i.e., cholesterol) and increase thermogenesis.20 Drugs are being developed for treatment of certain metabolic disorders commonly seen, such as obesity. One aspect of FGF21 that is exciting to researchers is its ability to stimulate the “browning” of white fat, which increases calorie burning and wasting of fatty acids as heat, instead of storing the excess calories as adipose (fat). This occurs via processes involving adrenergic stimulation and PGC-1alpha, a messenger that has been implicated in improving metabolic health in muscle and fat cells.21,22 Unfortunately, there is still much to learn about FGF21, as it is elevated in obesity and type 2 diabetes, suggesting that chronically elevated concentrations lead to either a state of resistance or activation pathologic pathways.20,23

 

It is likely that the pulsatile spikes in FGF21 produce its metabolic benefits, and there is evidence showing that depriving the diet of single amino acids (leucine, histidine, asparagine and methionine) causes the liver to produce FGF21 via the GCN2 pathway, the same pathway that controls feeding in the brain when diets are deficient in EAAs.12 Further, it has been shown that restricting dietary protein in rats AND HUMANS!!! produces a sharp increase in FGF21.24 The rats demonstrated increased hunger and energy expenditure. This effect was not seen when a protein-sufficient hypocaloric diet was given, demonstrating a specific effect for inadequate dietary protein.

 

Though hypothetical at this point, muscle hypertrophy and repair may also induce increases in FGF21. Recall that muscle serves as a storage pool for amino acids. If training and hormones combine to induce a state of ongoing hypertrophy and muscle protein synthesis, then muscle-based amino acid availability to the circulation (bloodstream) may decrease. When muscle is being driven to grow, it “hogs” the amino acids that would hold off triggering FGF21. The reduction in the amino acid alanine may mimic the effects seen in rodents who have reduced muscle catabolism due to a lack of corticoid receptors (stress hormone).25 Alanine and glutamine are the two most prevalent free-form amino acids in skeletal muscle, and leucine catabolism has been proposed to maintain alanine concentration. In plain English, if the muscle doesn’t let go of alanine during fasting periods, the liver might pump out FGF21 as if it were in a protein-deficient state. This has been shown to increase the breakdown of stored fat in the liver and fat cells.

 

This leaves us at a difficult point. Some suggest that feeding a protein-deficient diet may be beneficial to weight loss, as it stimulates the production of FGF21, with its metabolic advantages.26 However, it has already been shown that higher protein intake is associated with more efficient weight loss, with greater specificity toward fat loss. Also, protein-deficient diets, particularly those low in EAAs, increase appetite along with increasing calorie burning. Appetite control is one of the biggest hurdles for most individuals seeking to lose weight, and increasing dietary protein has been shown to improve appetite control.

 

In all likelihood, FGF21-based drugs will be developed. Though the FGF21 pathway shows great promise, there is much that remains to be learned before any firm recommendations can be offered.

 

References:

1. Pasiakos SM, Carbone JW. Assessment of skeletal muscle proteolysis and the regulatory response to nutrition and exercise. IUBMB Life 2014;66:478-84.

 

2. Leidy HJ, Clifton PM, et al. The role of protein in weight loss and maintenance. Am J Clin Nutr 2015 Apr 29. [Epub, ahead of print]

 

3. Haase AM, Prapavessis H. Social physique anxiety and eating attitudes in female athletic and non-athletic groups. J Sci Med Sport 2001;4:396-405.

 

4. Thiel A, Gottfried H, et al. Subclinical eating disorders in male athletes. A study of the low weight category in rowers and wrestlers. Acta Psychiatr Scand 1993;88:259-65.

 

5. Wycherley TP, Moran LJ, et al. Effects of energy-restricted high-protein, low-fat compared with standard-protein, low-fat diets: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2012;96:1281-98.

 

6. Fernstrom JD. Large neutral amino acids: dietary effects on brain neurochemistry and function. Amino Acids 2013;45:419-30.

 

7. Vikøren LA, Nygård OK, et al. A randomised study on the effects of fish protein supplement on glucose tolerance, lipids and body composition in overweight adults. Br J Nutr 2013;109:648-57.

 

8. Mobley CB, Fox CD, et al. Effects of protein type and composition on postprandial markers of skeletal muscle anabolism, adipose tissue lipolysis, and hypothalamic gene expression. J Int Soc Sports Nutr 2015 Mar 13;12:14(15 pp).

 

9. Hrupka BJ, Lin YM, et al. Small changes in essential amino acid concentrations alter diet selection in amino acid-deficient rats. J Nutr 1997;127:777-84.

 

10. Federman DG, Kirsner RS, et al. Pica: are you hungry for the facts? Conn Med 1997;61:207-9.

 

11. Bhatia MS, Gupta R. Pica responding to SSRI: an OCD spectrum disorder? World J Biol Psychiatry 2009;10:936-8.

 

12. Morrison CD, Laeger T. Protein-dependent regulation of feeding and metabolism. Trends Endocrinol Metab 2015;26:256-262.

 

13. Anthony TG, Gietzen DW. Detection of amino acid deprivation in the central nervous system. Curr Opin Clin Nutr Metab Care 2013;16:96-101.

 

14. Blouet C, Jo YH, et al. Mediobasal hypothalamic leucine sensing regulates food intake through activation of a hypothalamus- brainstem circuit. J Neurosci 2009;29:8302-11.

 

15. Anderson, S.A. et al. (1990) Dietary branched-chain amino acids and protein selection by rats. J. Nutr 1990;120:52-63.

 

16. Davidenko O, Darcel N, et al. Control of protein and energy intake - brain mechanisms. Eur J Clin Nutr 2013;67:455-61.

 

17. Fromentin G, Darcel N, et al. Peripheral and central mechanisms involved in the control of food intake by dietary amino acids and proteins. Nutr Res Rev 2012;25:29-39.

 

18. Schwarz J, Burguet J, et al. Three-dimensional macronutrient-associated Fos expression patterns in the mouse brainstem. PLoS ONE 2010;5:e8974(8 pp).

 

19. Belza A, Ritz C, et al. Contribution of gastroenteropancreatic appetite hormones to protein-induced satiety. Am J Clin Nutr 2013;97:980-9.

 

20. Iglesias P, Selgas R, et al. Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21. Eur J Endocrinol 2012;167:301-9.

 

21. Douris N, Stevanovic D, et al. Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice. Endocrinology 2015 Apr 29. [Epub, ahead of print]

 

22. Fisher FM, Kleiner S, et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012;26:271-81.

 

23. Woo YC, Xu A, et al. Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. Clin Endocrinol 2013;78:489-96.

 

24. Laeger T, Henagan TM, et al. FGF21 is an endocrine signal of protein restriction. J Clin Invest 2014;124:3913-22.

 

25. Shimizu N, Maruyama T, et al. A muscle-liver-fat signaling axis is essential for central control of adaptive adipose remodeling. Nat Commun 2015 Apr 1;6:6693.

 

26. Müller TD, Tschöp MH. Play down protein to play up metabolism? J Clin Invest 2014;124:3691-3.

 

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