In previous posts, I've discussed the concept of protein leverage. This is an idea, put forward by two Australian scientists, Stephen Simpson and David Raubenheimer that many species, including humans, regulate appetite with a higher sensitivity to protein than other nutrients. We each need some amount of calories, carbohydrate, fat and protein each day. Simpson and Raubenheimer showed through a host of experiments that it seems we are willing to overeat energy (excess carbs or fat) in order to get enough protein.

Since protein has declined a couple of percentage points over the last forty years, making our food a bit protein-dilute, we have been over-eating calories in order to gain enough of the limited protein for optimum reproduction, growth, and fertility. The obesity pandemic, according to the protein leverage hypothesis, is a side effect of this trade off.

The body reacts to increasing protein in the diet with a counter-regulation that decreases appetite, apparently in an effort to avoid protein excess, but how is this accomplished? Somehow the protein ingested, as it is broken down into its component amino acids, must be sensed, either by our individual cells or the brain. While the handling of the nitrogen contained in protein is thoroughly understood (the primary need for urination is to regulate nitrogen balance) sensing and controlling the concentration of the amino acids as they relate to our every day need for repair and growth is more mysterious. The hypothalamus, which coordinates a variety of nerve inputs related to hunger and satiety, also functions to monitor the blood. Through this monitoring, the hypothalamus acts as a nutrient sensor for glucose, fatty acids and amino acids and uses this information in co-ordination with gut satiety signals to control our feeding.

But the protein leverage hypothesis proposes that there is a very direct link between protein intake and calories consumed, that somehow protein has a different, more powerful effect on our metabolism than the other two macronutrients which are shown fluctuate much more, without harming health. How does protein affect calorie consumption?

Calories cannot really be said to exist outside of the lab. We don't burn calories in the body, we burn fat, protein and carbohydrate after they get digested and converted to energy. This energy takes the form of ATP within our body. So, we are not actually looking for a protein/calorie interaction, but rather a protein/ATP interaction. The question is whether we can find any mechanism which might link protein intake to ATP levels in our cells?

The difficulty with trying to study ATP is that the individual molecules exist only for moments within cells, as they are used perpetually to drive the chemical reactions that keep us alive, warm, repairing ourselves and growing. ATP can’t be measured in the blood, urine, or spinal fluid. It’ll be gone by the time you put a muscle biopsy under a microscope. For these reasons, we have always used “calories” and “joules” which denote heat energy as a stand-in for the energy we get from food. But this brings the limitation of not knowing how those lab measurements convert to our internal energy levels.

Recall that ATP stands for “adenosine Tri phosphate.” This molecule gives up one of its charged phosphate groups to become ADP, or “adenosine Di phosphate,” which quickly gets recharged to ATP or degrades further to AMP, “adenosine Mono phosphate.” It can best be considered one molecule that exists in three energy states:

AMP<-->ADP <--> ATP


It is the giving and taking of the phosphate groups that drives the vast majority of chemical reactions that constitute animal life. When ATP levels are high, we can replicate our DNA, form enzymes, grow our cell structures, repair damage, move our muscles, digest our food, type on our computers . . . whatever it is we need to do. As ATP gets used up, AMP levels rise and it is important that the body senses this, to turn down all of the activities above, which use up energy.

If a scientist were to dream up a molecule which might serve as an indicator of whole body energy status, he would be hard pressed to do better than AMPK. This molecule is part of a cascade of chemical reactions that are set in motioni when AMP levels rise in a cell, which is why it is called "AMP activated kinase" or AMPK for short. AMPK then acts to conserve cellular energy by slowing DNA replication, protein creation, cell growth and division, heat production, etc. It serves as a regulator of the activity within each cell, so that when available energy is running down, the cell slows down to preserve itself (this discussion based on Viollet 2010).

In addition to controlling cellular reactions, AMPK regulates the use of the our two main fuel sources: fat and carbohydrate. Because ATP is very closely related to the amount of glucose available, AMPK signals the cell to cease storing glucose as glycogen and to utilize fat metabolism instead of putting excess energy into storage. It also encourages glycogen breakdown to counteract the decreasing glucose concentration in the cell.

AMPK shown here, resting after a hard day of regulating cellular metabolism.


The AMPK molecule is conserved through nearly all species down to single-celled yeast which have a very simple metabolism: when glucose is available, yeast grow and divide, when it is absent, they shut down to remain alive. AMPK is the means by which they accomplish this sensing. It does the same job, with some refinements, in our more complicated bodies. Human AMPK activity is also modulated by ATP directly (which inhibits it) so that it can be considered a direct stand-in for the AMP:ATP ratio at any given moment. This makes it an excellent candidate for a whole body energy sensor and indicator.

AMPk has a counterpart, called mTOR, which is more active when levels of ATP are high in the cell.


AMPK activity <--AMP <--> ADP <--> ATP --> mTOR activity


mTOR has an inconvenient derivation for its name (for our current discussion) but we must break it down, because it helps to explain why too much protein might be problematic. mTOR stands for “mammalian target of rapamycin” because it was found after the fact, when researchers discovered the mechanism by which the medicine rapamycin works to inhibit immune responses. Rapamycin is a useful medicine for transplant patients because it turns down the body’s ability to reject the foreign tissue. It inhibits this immune response by stopping the quick cell growth needed by the blood’s antibody producing cells to fight infection or foreign bodies. Because mTOR serves to increase DNA reading, cell growth and reproduction when there is enough energy (acting exactly opposite to the action of AMPK)  blocking mTOR with rapamycin keeps the immune cells from ramping up to kill off the organ which has been transplanted.

When we aren't talking about the medicine, rapamycin however, mTOR's normal role in the cell is to sense and communicate that ATP levels in a cell are rising. mTOR turns on processes which reflect a nutrient rich state, such as copying DNA, encouraging cell growth and reproduction, reinforcing cellular structure, creating enzymes necessary for chemical reactions, storing excess glucose as glycogen, and generating heat along the way. In the same way that AMPK gets to work when AMP signals low energy, mTOR ramps up when ATP signals that energy is abundant. AMPK and mTOR are also thought to interact with each other directly, with AMPK acting to inhibit mTOR activity in order to shut down energy wasting processes more quickly.

With regard to the mechanism of protein leverage, it has been shown that amino acids directly affect the activity levels of both AMPK and mTOR. The amino acid leucine seems to exert the strongest signal to the cells that protein is present. It acts to turn off the actions of AMPK and turn on the actions of mTOR. This correlates well with the observation that protein is satiating: mTOR acts when nutrients are available and AMPK when they are absent.

Because amino acids seem to have this ability in a way that is not available to carbohydrate or fat, this may account for the mechanism of protein leverage. The body does not stop eating until it has what it wants. The protein leverage hypothesis is that protein is what it wants most. When enough protein is present, the signal that the cells are in good standing runs through mTOR and AMPK, telling the body that no more food is needed at that time.

Since both AMPK and mTOR pathways are carried out within cells and neither molecule travels through the body in the circulation, it would seem that neither could be considered a whole body energy sensor. However, these very same pathways are active in the hypothalamus which governs our energy regulation. In addition to receiving signals of nutrient status from the gut via the nervous system, the nerve cells of the hypothalamus, through their interaction with the blood, are subject to the same regulation by protein’s availability as every other cell in the body. In the presence of increased amino acids, the hypothalamus will have decreased AMPK activity and increased mTOR activity, reflecting a nutrient replete status. The AMPK and mTOR activity levels in the hypothalamus may be the key to understanding why protein satisfies hunger and may be the mechanism by which the protein leverage effect occurs.

Because so much of our attention, when it comes to nutrition questions, is focused on the problem of obesity, any new possible solution is bound to be greeted with enthusiasm. Increasing protein in the food supply is a possible means of slowing or reversing obesity rates. Protein bars and shakes are everywhere you look now and it seems that "high protein" is the new "low carb" or "low fat." However, the pathways we have just brought into the discussion can serve to highlight how intricately balanced are the factors related to energy consumption and our overall health. If protein consumption decreases appetite by significantly altering the activity of such ubiquitous molecules as AMPK and mTOR, it is highly unlikely that it could do this without having unexpected consequences.

I have always counseled patients that, in my opinion, weight loss medications don’t seem to work and if one were ever to work well, you wouldn’t want to take it, because it could only do so by disrupting many body systems at once, causing problems perhaps worse than obesity. The possibility that the same could be true for protein needs to be examined before we celebrate the changes we are seeing in the food supply.

REFERENCE: Viollet B. et al. AMPK inhibition in health and disease. Critical Reviews in Biochemistry and Molecular Biology 2010, 45(4): 276-295.