Non-essential amino acids influence the brain in a way that curbs appetite and promotes exercise

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In experiments on mice, researchers at ETH Zurich show that non-essential amino acids act as appetite suppressants and promote the urge to move. Their research is published in Current Biology and provides insight into the neural mechanism that controls this behavior.

Proteins can suppress appetite, so a protein-rich diet can help people lose weight. That’s just one of the reasons why this kind of diet has become increasingly popular in recent years. Working with mice, researchers at ETH Zurich have now demonstrated a new mechanism by which the building blocks of proteins – the amino acids – curb appetite. Specifically, it involves what are known as non-essential amino acids.

Of the 21 amino acids our bodies require, there are nine they are unable to produce on their own. They are called essential amino acids. Because we must obtain these through our diet, they have long been the focus of nutrition research. The other 12 amino acids are considered non-essential. The body can produce them itself by altering other molecules.

Shown in mice

It has been known that both essential and non-essential amino acids can suppress appetite. However, for the non-essential amino acids, the mode of action had not yet been demonstrated in living organisms. Now, a group of researchers led by Denis Burdakov, professor of neuroscience at ETH Zurich, have shown for the first time in a living organism that the non-essential amino acids influence the brain in a way that curbs appetite and promotes exercise.

The researchers first fed mice either a mixture of various non-essential amino acids or a sugar solution with the same amount of calories (control group). Both groups of mice were then allowed to drink a milkshake, which they normally love. While the control group drank copious amounts of it, the mice that had been fed non-essential amino acids avoided theirs. Instead, they went around their enclosure in search of alternative sustenance.

Rooted in evolutionary history

With additional experiments, the researchers were able to decode the underlying mechanism, in which specialized nerve cells in the brain – orexin neurons – play the main role. Proteins that the mice take in through food are broken down in the gut into their amino acids, which then enter the bloodstream. From there, the blood transports them to the brain.

The orexin neurons in the hypothalamus have receptors that specifically recognize the non-essential amino acids. In response, they initiate a neural circuit that produces the described behavioral changes.

This mechanism is likely rooted in evolutionary history. “Today, we have sufficient access to all nutrients, and we have plenty of time for eating. In prehistoric times, when this mechanism developed, that was likely not the case,” says Paulius Viskaitis, a postdoc in Burdakov’s group and lead author of the study.

“Back then, it was advantageous for individuals to spend only a short amount of time at a food source that consisted primarily of non-essential amino acids.” If eating non-essential amino acids promotes the urge to move, the animal will go in search of other sources of food—which potentially contain more essential nutrients and are more important for the individual.

Viskaitis stresses that the results are transferable to humans and other animals, as this mechanism affects a region of the brain that is very old in terms of evolutionary history and occurs equally in all mammals and many other vertebrates. Still, for people who want to lose weight, a diet that includes especially many non-essential amino acids cannot be recommended across the board, Viskaitis says. Nutritional recommendations should be made on an individual basis, and they should also take health aspects into account.


Introduction: Protein as Unique Nutrient Providing Essential Amino Acids

Animals eat to procure nutrients, with the hallmark example being the need to procure energy (calories). The restriction of energy intake induces a negative energy balance, which triggers a variety of adaptive responses that collectively mitigate the effects of continued energy restriction and serve to rapidly restore energy balance when food becomes available.

For instance, energy expenditure is reduced to conserve remaining energy stores, the motivation to find and consume food is increased, and short-term satiety signals (such as gut distension) have a diminished effect, resulting in larger meals once the food is consumed.

Many reviews have covered the homeostatic regulation of energy balance, and it is well accepted that a variety of hormones act as nutritional signals and engage neural circuits controlling feeding behavior and energy expenditure [1,2,3,4,5,6,7,8,9,10,11].

However, do animals only defend against energy restriction? For example, it has been widely demonstrated that the depletion of sodium triggers robust physiological (increased sodium retention) and behavioral (increased sodium consumption) adaptations that act to restore sodium balance [12,13,14,15].

Among the three macronutrients, dietary protein is unique in its capacity to provide essential amino acids. Essential amino acids are necessary for survival but cannot be synthesized by mammals and thus are required in the diet. While carbohydrate and lipid act primarily as sources of energy (and essential fatty acids in that case of fat), protein can provide both energy (amino acids can be metabolized) and essential amino acids.

It is also a misnomer to think of protein as a single, monolithic macronutrient. Protein is a complex mixture of amino acids, and thus, dietary protein sources can vary in their quality, with high-quality protein sources providing balanced ratios of essential and non-essential amino acids that meet nutritional needs, while low-quality protein sources provide imbalanced ratios often with excess non-essential amino acids.

It should be noted that this review’s focus on protein relates primarily to omnivores, which balance intake across a wide variety of food sources. Herbivores (such as a variety of ruminant species) or obligate carnivores (such as cats) exhibit distinct physiological and behavioral adaptations fitted to their unique nutritional requirements [16].

Protein’s role as the only source of essential amino acids naturally leads to the possibility that protein status is monitored or defended, such that animals react both physiologically and behaviorally to the restriction of protein intake and the resultant negative protein balance [17,18,19,20,21].

We and others have written extensively on this topic in recent years, with the consensus being that a variety of species do ‘defend’ protein in a manner that is loosely similar to the defense of energy or sodium [22,23,24,25,26,27,28,29,30,31]. For example, variations in amino acid intake lead to adaptive metabolic changes in the liver, which conserve amino acids during periods of scarcity and metabolize amino acids during periods of excess [32,33,34,35,36,37,38,39,40,41,42].

Thus, the liver serves to buffer against marked changes in circulating amino acids, which is somewhat analogous to its role in minimizing fluctuations in circulating glucose. This important role of the liver in maintaining amino acid balance is relevant when considering that the liver is the primary source of circulating fibroblast growth factor 21 (FGF21; see below). Similarly, variations in dietary protein content also alter feeding behavior, with high-protein diets tending to suppress food intake and low-protein diets tending to increase food intake [28,29,30,31,43,44].

Several labs including our own have demonstrated that rodents on a low-protein diet exhibit spontaneous changes in ‘macronutrient selection’, such that they selectively increase the consumption of high-protein foods while reducing the consumption of food with high carbohydrate or fat [45,46,47,48]. Finally, several studies in humans have also suggested that protein acceptance or preference is increased when total protein intake is low [49,50,51,52,53].

The general observation that low-protein diets drive adaptive changes in food intake or preference is also consistent with the protein leverage hypothesis, which argues that animals prioritize protein intake and as such will overconsume energy to meet protein needs when exposed to low-protein diets [44,54,55]. Observations in a variety of species, including humans, are consistent with this basic observation [56,57,58], although the effect has not been observed universally and varies based on the species and physiological context [44,59,60,61].

With this basic introduction, the remainder of this review will focus on mechanisms that might mediate the ability to adaptively shift food preference in response to insufficient protein intake. In particular, this review will focus on the concept that the induction of a protein-specific appetite in response to a protein need state is likely mediated by two discrete but interacting mechanisms, the first linked to long-term signals of protein need, and the second linked to acute meal-related signals that allow the organism to distinguish between foods based on their protein content.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620426/


More information: Paulius Viskaitis et al, Ingested non-essential amino acids recruit brain orexin cells to suppress eating in mice, Current Biology (2022). DOI: 10.1016/j.cub.2022.02.067

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