Impacts of essential amino acids on energy balance
Obesity develops due to an imbalance in energy homeostasis, wherein energy intake exceeds energy expenditure. Accumulating evidence shows that manipulations of dietary protein and their component amino acids affect the energy balance, resulting in changes ...
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Abstract
Background
Obesity develops due to an imbalance in energy homeostasis, wherein energy intake exceeds energy expenditure. Accumulating evidence shows that manipulations of dietary protein and their component amino acids affect the energy balance, resulting in changes in fat mass and body weight. Amino acids are not only the building blocks of proteins but also serve as signals regulating multiple biological pathways.Scope of review
We present the currently available evidence regarding the effects of dietary alterations of a single essential amino acid (EAA) on energy balance and relevant signaling mechanisms at both central and peripheral levels. We summarize the association between EAAs and obesity in humans and the clinical use of modifying the dietary EAA composition for therapeutic intervention in obesity. Finally, similar mechanisms underlying diets varying in protein levels and diets altered of a single EAA are described. The current review would expand our understanding of the contribution of protein and amino acids to energy balance control, thus helping discover novel therapeutic approaches for obesity and related diseases.Major Conclusions
Changes in circulating EAA levels, particularly increased branched-chain amino acids (BCAAs), have been reported in obese human and animal models. Alterations in dietary EAA intake result in improvements in fat and weight loss in rodents, and each has its distinct mechanism. For example, leucine deprivation increases energy expenditure, reduces food intake and fat mass, primarily through regulation of the general control nonderepressible 2 (GCN2) and mammalian target of rapamycin (mTOR) signaling. Methionine restriction by 80% decreases fat mass and body weight while developing hyperphagia, primarily through fibroblast growth factor 21 (FGF-21) signaling. Some effects of diets with different protein levels on energy homeostasis are mediated by similar mechanisms. However, reports on the effects and underlying mechanisms of dietary EAA imbalances on human body weight are few, and more investigations are needed in future.Introduction
In recent decades, obesity has become a global public health concern. Between 1975 and 2016, the prevalence of obesity increased at an alarming rate in children and adolescents from 0.7% to 5.6% in boys and 0.9% to 7.8% in girls worldwide [1]. The prevalence of obesity increased from 3.2% to 10.8% in adult men and from 6.4% to 14.9% in adult women between 1975 and 2014 [1]. Obesity has also been associated with many other diseases, including diabetes, cardiovascular diseases, and hypertension. These conditions lead to reduced life quality and several social problems. One of the important factors that contribute to obesity is the dietary macronutrients, including fat, carbohydrate, and protein. Therefore, studies on effective dietary interventions to address obesity are gaining momentum.Among the three macronutrients, fat and carbohydrate contents were thought particularly relevant in obesity previously. Increasing evidence has shown that dietary protein is also important in regulating body weight. Both low- and high-protein diets have been shown to promote weight loss. It seems controversial that the two diets do not demonstrate opposite effects and remains unknown how the two diets bring about similar changes to body weight. After consumption, proteins are hydrolyzed into single amino acid and peptides. The effects of a protein depend on its various constituent amino acids. It has been postulated that certain amino acids may mediate the metabolic effects of diets with different protein levels [[2], [3], [4], [5], [6]]. Alterations of certain amino acid intake could attenuate the effects of these protein diets on body weight. In addition, diets lacking or supplemented with a single amino acid may produce a similar physiological response to that observed following low- or high-protein diets. In this respect, manipulating the dietary composition of amino acids merits careful investigation.
Amino acids are classified as essential and non-essential. Dietary proteins are the key sources of essential amino acids (EAAs). Humans can synthesize non-essential amino acids endogenously. There are nine EAAs namely, leucine (Leu), isoleucine (Ile), valine (Val), phenylalanine (Phe), threonine (Thr), tryptophan (Trp), methionine (Met), lysine (Lys), and histidine (His). Among all EAAs, Leu, Ile, and Val are known as branched-chain amino acids (BCAAs), which have aliphatic side chains (a central carbon atom bound to ≥3 carbon atoms). Accounting for around 40% of the total amino acid requirement in the body, BCAAs have received considerable attention over the last decade because of their ability to promote protein synthesis and to affect metabolism. Recently, it has been proven that EAAs are not only the building blocks of proteins but also work as signaling molecules regulating multiple biological processes.
Obesity is often considered an outcome of energy imbalance with excessive energy intake and insufficient energy consumption [7]. Several central and peripheral factors are involved in energy homeostasis. A better understanding of mechanisms underlying the effects of EAAs in energy homeostasis will help to provide new intervention strategies for obesity treatments. This review aims to present the currently available knowledge on the key role played by individual EAA in body weight and energy balance as signaling molecules. Notably, the mentioned metabolic aspects here refer to adult mammals, as the relative importance of EAAs differs for growing mammals. This review will deepen understanding of the physiological function of EAAs and the related underlying mechanisms.
The effects of essential amino acid deprivation or restriction on body weight and energy balance
Numerous studies have reported that dietary EAA deprivation or restriction causes profound alterations in energy balance, resulting in remarkable changes in fat mass and body weight. Researchers have noticed that animals fed a diet devoid of an EAA exhibited a loss of body weight a long time ago. In rats, the extent of weight loss differs upon omission of different amino acids [8]. In these early studies, researchers have mainly focused on the effect of EAA deprivation on protein metabolism. During the last 20 years, the role of amino acids in regulating energy homeostasis has emerged. Here, we review the literature related to the effects of EAA deprivation or restriction on body weight and energy balance (Table 1).Table 1
The effects of essential amino acids on energy balance.| Diet | The effects on energy balance | Studies |
|---|---|---|
| Histidine deprivation | Chow diet Body weight and Fat mass↓ | [8] |
| Isoleucine deprivation | Chow diet Body weight and Fat mass↓ Food intake↓ Energy expenditure↑ Brown adipose tissue uncoupling↑ | [10] |
| Leucine deprivation | Chow diet Body weight and Fat mass↓ Food intake↓ Energy expenditure↑ White adipose tissue lipolysis and browning↑ Brown adipose tissue uncoupling↑ | [9,40,63] |
| Lysine deprivation | Chow diet Body weight and Abdominal fat↓ Food intake↓ Energy expenditure↑ | [12] |
| Methionine deprivation | Chow diet or high-fat, high-sucrose diet Body weight and Fat mass↓ Energy expenditure↑ | [11,12] |
| Phenylalanine deprivaiton | Chow diet Body weight and Fat mass↓ Food intake↓ Energy expenditure↑ | [12] |
| Threonine deprivation | Chow diet Body weight and Fat mass↓ Food intake↓ Energy expenditure↑ | [12] |
| Tryptophan deprivation | Chow diet Body weight and Fat mass↓ Food intake↓ Energy expenditure↑ | [8,12] |
| Valine deprivation | Chow diet Body weight and Fat mass↓ Food intake↓ Energy expenditure↑ Brown adipose tissue uncoupling↑ | [10,13] |
| Isoleucine restriction | Chow diet or high-fat, high-sucrose diet Body weight and Fat mass↓ Food intake↑ Energy expenditure↑ White adipose tissue browning↑ | [4] |
| Leucine restriction | Chow diet Body weight and Fat mass↓ | [[29], [30], [31]] |
| Methionine restriction | Chow diet or high-fat diet: Body weight and Fat mass↓ Food intake↑ Energy expenditure↑ White adipose tissue lipogenesis and lipolysis↑ Brown adipose tissue uncoupling↑ | [[18], [19], [20],26,29,34,35] |
| Threonine restriction | Chow diet Body weight and Fat mass↓ Food intake↑ Energy expenditure↑ | [6] |
| Valine restriction | High-fat, high-sucrose diet Body weight and Fat mass↓ Food intake↑ Energy expenditure↑ | [4] |
| Histidine supplementation | Chow diet or high-fat diet Body weight and Fat mass↓ Food intake↓ | [108,109] |
| Isoleucine supplementation | High-fat diet Body weight and Fat mass↓ Food intake— White adipose tissue browning↑ | [114,119] |
| Leucine supplementation | High-fat diet Body weight and Fat mass↓ Food intake— Energy expenditure↑ White adipose tissue browning↑ | [2,114,116,117] |
| Lysine supplementation | Chow diet Body weight and Food intake↓ | [106,107] |
| Phenylalanine supplementation | High-fat diet Body weight and Food intake↓ | [110] |
| Threonine supplementation | High-fat diet Body weight and fat mass↓ Food intake— Brown adipose tissue uncoupling↑ |
Essential amino acid deprivation or restriction and body weight
Dietary deprivation of any single EAA is known to reduce fat mass and body weight in rodents [[8], [9], [10], [11], [12], [13]]. Diets devoid of BCAA have received utmost attention, as numerous studies have shown increased circulating BCAA levels in obese human and animal models [12,[14], [15], [16]]. Given that the complete deprivation of one EAA has adverse long-term health effects, people have investigated the optimal concentration of dietary EAAs that can reduce body weight without causing severe negative effects. To date, most work on the dietary restriction of an EAA has focused on Met. The effects of dietary Met restriction are well established. Much of the work about Met restriction began with the original report in 1993 that a diet low in Met (0.17% of diet [w/w] compared with 0.86% in controls) increased the life span of rats [17].Accumulating evidence has demonstrated that in addition to enhancing longevity, 80% Met restriction decreases fat mass and body weight while developing hyperphagia [[18], [19], [20]]. Short-term (4–12 weeks) or long-term (80 weeks) consumption of the 80% Met restricted diet could produce the above-mentioned effects in growing, adult, or aging rats [[20], [21], [22]]. While most of the early studies on dietary Met restriction were performed in rats, subsequent studies with mice have shown that the responses to Met restriction are comparable in almost every respect [23]. To date, the effects of Met restriction on metabolic health have been the subject of several reviews [[23], [24], [25], [26]].
Studies have demonstrated that decreased consumption of BCAAs promotes fat loss and weight normalization [4,5,27,28]. Furthermore, restriction of only Leu [[29], [30], [31]] or Ile [4] has been shown to reduce fat accumulation and body weight. However, a recently published study reported that restriction of Leu did not produce these beneficial metabolic effects [4]. An important reason responsible for the different observations may be the different Leu concentrations in control diets. The earlier studies [[29], [30], [31]] used a control diet containing 1.11%–1.2% Leu, while the Leu concentration was 2.54% in the control diet in a latter study [4]. Moreover, to make all the diets isocaloric with equal fat levels, the carbohydrate level of the Leu-restriction diet was increased in the previous study, while the non-EAA levels of the Leu-restriction diet were increased in the latter study. Thus, the metabolic phenotype of the control mice might have shown a difference, and the degree of Leu restriction was not the same in these studies. Besides Met and BCAAs, some other EAAs have also been evaluated. For example, dietary Trp or Thr restriction decreases fat mass and body weight in rodents [6,32].
Essential amino acid deprivation or restriction and energy balance
Diets deficient in an EAA have long been known to reduce food intake in animals [9,10,12,13,33]. Studies on Leu deprivation included a pair-fed group by feeding mice the control diet in the amounts consumed by the Leu-deprivation group [9]. A minor decrease in average body weight was observed in the pair-fed mice, but the fat mass was similar to that in the control mice, suggesting that the observed weight reductions in Leu-deprived mice are primarily due to the increased energy expenditure, rather than due to the small reduction in food intake [9]. However, it remains unclear whether this is also the case for other EAA deprivation. In contrast, dietary Met [19,34,35], Ile [4] or Thr [6] restriction significantly increase food consumption, although these diets induce weight loss. This implies that Met, Ile, or Thr restriction reduces fat deposition without calorie restriction, and the excess food intake is largely dissipated as heat rather than incorporated as fat.Dietary limitations of EAAs also affect whole-body energy expenditure, as observed using data from metabolic cages [4,[9], [10], [11], [12],19,20,27,28]. Deprivation of a single EAA [[9], [10], [11], [12]] and restriction of Met, Ile, or Thr [4,6,19,20,36] have been shown to increase energy expenditure. The higher energy expenditure may be caused by the activation of thermogenesis and mediated by brown adipose tissue (BAT) and the browning of white adipose tissue (WAT). Generally, adipocytes can be divided into white, brown, and beige fat cells [37]. BAT is a key site of heat production (thermogenesis) in mammals [38]. Some brown fat-like cells may appear in the WAT under external stimulation, including some nutrients. These inducible cells are called “beige cells”, and this process is known as white fat browning [39]. WAT stores chemical energy as triglycerides. Both brown and beige fat cells contain uncoupling protein-1 (UCP1), which functions to generate heat via uncoupling respiration from adenosine diphosphate (ADP) phosphorylation in the mitochondria [38]. Increasing energy expenditure through stimulation of BAT and WAT browning has been considered as a good strategy to promote weight loss. Deprivation of a BCAA [9,10,13,40] and restriction of Met or Ile [4,20] have been proven to upregulate UCP1 expression in BAT and WAT, suggesting increased thermogenesis. Additionally, Met restriction could not increase energy expenditure or reduce adiposity in Ucp1/- mice [41]. These findings strengthen the view that changes in BAT and WAT thermogenesis account for the increased energy expenditure and fat loss under these diets.
Besides, a link between dietary limiting EEAs and lipid metabolism has been demonstrated. Individual BCAA deprivation stimulates lipolysis and the expression of β-oxidation genes and decreases the expression of lipogenic genes and the activity of fatty acid synthase (FAS) in WAT, consistent with increased use and decreased synthesis of fatty acids, respectively [9,10]. Recent studies have shown that Met [42] and Leu [30] restriction also alters lipid metabolism, including lipid synthesis and lipolysis pathway in WAT. Particularly, Met restriction increases both lipogenesis and lipolysis in WAT, leading to a lipid–futile cycle [26]. The enhanced lipid cycling consumes more potential energy as heat, which could partially explain the increased energy expenditure [29].
