Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution

Abstract

Dietary protein dilution (DPD) promotes metabolic-remodelling and-health but the precise nutritional components driving this response remain elusive. Here, by mimicking amino acid (AA) supply from a casein-based diet, we demonstrate that restriction of dietary essential AA (EAA), but not non-EAA, drives the systemic metabolic response to total AA deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Dietary threonine restriction (DTR) retards the development of obesityassociated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.

Effects of Short-Term Dietary Protein Restriction on Blood Amino Acid Levels in Young Men

“…Here, we show that, particularly during meal feeding tests, the blood plasma levels of essential amino acids isoleucine, leucine, valine (i.e., branched chain AA), lysine, phenylalanine, and threonine, as well as the non-essential AA tyrosine, were lower in young men undergoing DPR compared with their habitual diet. A similar signature was found in our former studies of mice [9,17], demonstrating mammalian conservation of these responses. Additionally, this AA signature is reminiscent of several studies that have shown higher blood levels of these amino acids as predictive of current or future type 2 diabetes risk in humans [19][20][21].…”

“…Indeed, THR restriction without total AA restriction mimics the effects of DPR in mice, without the negative side-effects of reduced skeletal muscle mass [17]. In addition, we previously demonstrated that dietary THR restriction improves metabolic health in a pre-clinical mouse model of obesity driven type 2 diabetes [17]. Thus, future studies should closely examine the effects dietary threonine restriction in humans.…”

“…Thus, given that THR was the most limiting EAA identified ( Figure 6) and its blood levels were lower with DPR (Figure 4), it is likely that the restriction of THR alone to levels within DPR would mimic the effects of DPR. Indeed, THR restriction without total AA restriction mimics the effects of DPR in mice, without the negative side-effects of reduced skeletal muscle mass [17]. In addition, we previously demonstrated that dietary THR restriction improves metabolic health in a pre-clinical mouse model of obesity driven type 2 diabetes [17].…”

“…Multiple studies have shown that dietary protein restriction promotes metabolic health via restriction of dietary amino acids. In particular, we have recently shown that restriction of essential amino acids is both sufficient and necessary to confer the metabolic remodeling that occurs with dietary protein restriction (DPR) in mice [17], less information about which amino acids do so in humans. Here, we show that, particularly during meal feeding tests, the blood plasma levels of essential amino acids isoleucine, leucine, valine (i.e., branched chain AA), lysine, phenylalanine, and threonine, as well as the non-essential AA tyrosine, were lower in young men undergoing DPR compared with their habitual diet.…”

“…We have preciously demonstrated in mice, using casein-based diets, that the restriction of EAAs, particularly THR and TRP, was necessary and sufficient to confer the metabolic effects of DPR [17]. Thus, even though certain NEAAs were deemed to be the most limiting according to in silico exome matching ( Figure 6), this is likely to be inconsequential [17]. LEU, MET and THR were shown to be the most limiting EAAs (Figure 6).…”