Mechanisms of satiation with a short-term high-protein diet

Sustained satiety is a key component to induce a negative energy balance and to promote weight loss. An ideal weight loss strategy would promote satiety and maintain basal metabolic rates despite a negative energy balance and reduction in fat-free mass. Satiety is multifactorial and influenced by many components including but not limited to the endocrine system, the cognitive and neural system as well as the gastrointestinal system. A diet high in protein seems to be able to influence certain systems. The hierarchy for macronutrient-induced satiating efficiency is similar to that observed for diet-induced thermogenesis (DIT): protein is the most satiating macronutrient followed by CHOs and fat, which is least satiating [7]. This satiating effect is most significant after high-protein diets [8]. Based on a visual analogue scale (VAS), which comprises a standard tool to measure subjective appetite and satiety [9], satiety was significantly greater after a 60% protein meal than after a 19% protein meal [10]. These findings were confirmed by Crovetti et al. who reported significantly greater satiety after consumption of an isocaloric meal containing 68% protein compared with a 10% protein meal [11]. Increased satiety helps to decrease energy intake, which is a requisite for successful weight loss. In general, increased satiety has been observed after meals with a protein content in the range of 25% to 81% [12].

Interestingly, different types of protein induce distinct effects on satiety and responses of (an)orexigenic hormones. Also the mechanism of satiety is different, especially for whey and casein proteins. Hall et al. compared whey and casein protein and reported decreased energy intake from a buffet meal offered after 90 min after whey protein ingestion, indicating an increased satiety response to whey [13]. As the absorption of casein is slower due to clot formation, 90 min may be too short to make the conclusion of increased satiety. Veldhorst et al. [14] compared the satiating effects of either 10% or 25% of energy from casein-, soy-, or whey-protein. At 10%, whey provoked the strongest reduction in hunger followed by casein and soy. Decreased hunger rates coincided with higher leucine, lysine, tryptophan, isoleucine, and threonine responses with this protein type. For the 25% protein intake, the authors report larger responses in hormone concentrations for whey-protein as compared to casein- or soy-protein. When Hochstenbach-Waelen et al. [15] compared the effects of 2 diets with either 25% or 10% of energy from casein, they report increased energy expenditure, protein balance, satiety, and negative fat balance with the 25% casein diet as compared to the 10% diet, indicating a dose-dependent satiating effect for this type of protein. Diepvens et al. [16] examined the effects of whey protein, pea protein hydrolysate, a combination of whey protein and pea protein hydrolysate and control milk protein (80% casein and 20% whey) on appetite ratings and satiety hormones. They found that pea protein hydrolysate was most effective in suppressing hunger, followed by whey protein, as compared to milk protein. Surprisingly, these findings do not correlate with changes in satiety hormones, which were stimulated more by milk proteins, indicating that peptide hormone response does not always correlate with perceived satiety. Nieuwenhuizen et al. [17] hypothesized that tryptophan (Trp) which serves as a precursor for the anorexigenic neurotransmitter serotonin, would contribute to the satiating effect of this amino acid in dietary proteins. When comparing alpha-lactalbumin (high in Trp), gelatin (low in Trp) or gelatin with added Trp (high in Trp), the authors report that the breakfast containing alpha-lactalbumin suppressed hunger more than a gelatin or gelatin + trypthophan breakfast. This observation, however, was independent of Trp concentrations. In conclusion, it seems that different types of proteins exert distinct effects on satiety and appetite ratings, mediated by a nutrient-specific secretion of hormones. These differences between the proteins seem to be related to timing and certain amino acid threshold levels.

To assess the nutritional value of dietary proteins considering the protein source and dietary indispensable amino acid content, the digestible indispensable amino acid score (DIAAS) has been established as a new protein quality measure to replace the protein digestibility-corrected amino acids score (PDCAAS) [18]. It is derived from the ratio between the amount (mg) of digestible dietary indispensable amino acid in 1 g of the dietary protein and the amount (mg) of the same dietary indispensable amino acid in 1g of the reference protein. The DIAAS can have values below or in certain circumstances above 100%. Values above 100% should not be truncated as was done for the PDCAAS [19], except when the DIAAS is calculated for protein or amino acid intakes for mixed diets or sole source foods. In general, protein quality, digestibility and utilization by the human body is highest in proteins from animal sources such as meat, milk and egg, followed by legume plant protein such as soy with cereal protein such as wheat concluding this list [20].

Several factors contribute to increased protein-induced satiety in response to a short-term high-protein intake. The most important ones seem to be i) increased energy expenditure, increased concentrations of ii) anorexigenic hormones, and iii) metabolites such as amino acids and iv) altered gluconeogenesis. High protein diets can therefore favorably alter the energy balance equation. Enhanced satiety allows for decreased food intake while an increased thermic effect allows for greater calorie output.

The effect of a high-protein diet on body composition and weight loss

With regard to the macronutrient distribution, it appears that there is a difference whether protein is increased at the expense of CHO or fat. Increasing protein at the expense of CHOs leads to increased contribution of amino acids to energy expenditure with a concomitant decrease in lipogenesis due to decreased supply of dietary glucose [68] and likely has a negative impact on exercise performance and training intensity [69]. Carbohydrate supply is critical for strength and endurance performance. Athletes should therefore be aware about limited energy intake and maintenance of training levels. For obese subjects, lowering carbohydrate in favor of protein might be advantageous as dietary CHOs might impair fat oxidation [70] whereas low-CHO, high-protein diets reduce adipose tissue development [71]. Higher daily protein intake at the expense of fat intake could substantially reduce total energy intake, which could possibly translate to a healthier weight status [72].

Long-term effects of high-protein diets depend on the population studied as well as the exact composition of the diet but have generally been shown to include weight reduction and weight loss maintenance as well as beneficial effects on metabolic risk factors such total cholesterol and triacylglycerol. Claessens et al. [73] compared a low-fat, high-carbohydrate diet against a low-fat, high-protein diet. The authors conclude that after 12 weeks of diet intervention, the low-fat, high-protein diet was more effective for weight control. Clifton et al. [74] analyzed data from 215 obese subjects which were either assigned to a 12 week high-protein or standard-protein diet. The authors conclude that subjects in the high-protein group had beneficial effects on total cholesterol and triacylglycerol and achieved greater weight loss and better lipid results. In another study, Clifton et al. [75] determined the efficacy of a high-protein and high-carbohydrate intake on the maintenance of weight loss after 64 weeks of follow-up. The authors found no significant difference between groups regarding weight loss. Protein intake in grams derived from the dietary records, however, was directly related to weight loss [75]. Westerterp-Plantenga et al. [76] studied that effect of a 20% higher protein intake (18% of energy vs 15% of energy) for subsequent 3 months of weight maintenance after weight loss. They found that higher protein intake resulted in a 50% lower body weight regain over this time, possibly related to increased satiety and decreased energy efficiency [76]. It has to be mentioned, however, that a hypochaloric diet with a high protein content of 20-30% is only relatively high in protein compared to a eucaloric diet with a normal protein level of 10-15% while the absolute amount of protein often does not differ between the two diets [77].

The mechanisms by which increased long-term dietary protein intake regulate body weight are not well understood but are most likely multifactorial. Depending on the diet, lower triacylglycerol levels and hence fat mass loss with a higher-protein diet as well as increased satiety possibly mediated by increased leptin sensitivity have been discussed [75, 78, 79]. Fluid loss related to reduced carbohydrate intake and overall caloric restriction have also been discussed to mediate weight loss [5].

Possible caveats of a high-protein diet

Metabolomics studies revealed that high intake of branched-chain amino acids (BCAAs, Valine, Leucine, Isoleucine) and aromatic amino acids (Phenylalanine, Tyrosine) may be associated with the development of metabolic diseases [80]. Importantly, this only occurs in combination with a high-fat diet. BCAA supplementation contributes to accumulation of intermediates propionyl-CoA and succinyl-CoA, which are a catabolic byproduct of BCAA degradation. High catabolic flux of these intermediates interferes with appropriate oxidation of fatty acids, possibly by allosteric inhibition of citrate synthase [81] which slows down the TCA cycle, causing buildup of incompletely oxidized substrates such as acylcarnitines. This accumulation leads to mitochondrial stress, impaired insulin action, and finally to perturbation of glucose homeostasis [80]. This connection might be highly relevant as many overweight people worldwide are effectively on a high-fat diet but might as well do weight-training and supplement with BCAAs. Therefore, in people with a high caloric intake from fat BCAA supplementation might exacerbate the risk of metabolic disease.

Diets high in protein pose a potential acid load to the kidneys, mainly as sulfates and phosphates [82]. It was hypothesized that calcium and hence bone mass was lost in order to buffer this acid load [83]. Although the bone-loss hypothesis has been refuted and there is agreement that high-protein diets are actually favorable to intestinal calcium uptake, bone health and bone mineral density [84], the protein-induced acid-load to the kidneys remains, e.g. as sulfuric acid from the oxidation of methionine and cysteine. This phenomenon is especially prominent in diets such as the Atkins diet which can lead to additional acid buildup from ketone bodies in response to reduced carbohydrates and concomitantly increased fat and protein intake. Frank et al. [85] assessed the effect of short-term increased oral protein ingestion on renal function, hemodynamics, and clinical-chemical variables in healthy young men. They reported significant changes in the glomerular filtration rate, the filtration fraction, albuminuria, serum uric acid, and urinary pH values in the high-protein diet group. The authors conclude that renal hemodynamics and renal excretion is altered in response to a short-term, high-protein diet. Although depended on the source of protein, interventional studies in humans have shown that high-protein diets have the potential to increase the risk of calcium stone-formation in the urinary tract [82, 86]. In order to maintain an acid–base balance in the body, people on a high-protein diet should consider ingestion of alkali buffers such as fruits and vegetables high in potassium (alkaline-forming foods). Glutamine or sodium bicarbonate supplements can also help to restore acid–base balance in the body. In general, people experimenting with high-protein diets are advised to monitor their renal function.

People on high-protein diets are advised to choose their source of protein very carefully (i.e. emphasize the use of high-quality protein sources from plant origin). Many protein-rich foods of animal origin (e.g. red meats, eggs and dairy products) also contain high levels of saturated fats and cholesterol. This may put consumers of high-protein diets at higher risk for heart disease, hyperlipidemia and hypercholesterolemia [87]. Healthier proteins from vegetables (soy protein, beans, tofu, seitan or nuts) or fish could be a valuable alternative. Finally, all excess protein will eventually be converted to glucose (via gluconeogenesis) or ketone bodies [88, 89]. This may also explain the increased gluconeogenesis in response to a high-protein diet, as described above. In a state of low energy demand, these metabolites will be stored as glycogen and fat, which is undesirable if weight loss is the goal. Along these lines, weight loss can only be achieved by establishing a negative calorie balance, though this may be more tenable on a high-protein diet.