Regulation of metabolic health by essential dietary amino acids

Abstract

Although the beneficial effects of calorie restriction (CR) on health and aging were first observed a century ago, the specific macronutrients and molecular processes that mediate the effect of CR have been heavily debated. Recently, it has become clear that dietary protein plays a key role in regulating both metabolic health and longevity, and that both the quantity and quality - the specific amino acid composition - of dietary protein mediates metabolic health. Here, we discuss recent findings in model organisms ranging from yeast to mice and humans regarding the influence of dietary protein as well as specific amino acids on metabolic health, and the physiological and molecular mechanisms which may mediate these effects. We then discuss recent findings which suggest that the restriction of specific dietary amino acids may be a potent therapy to treat or prevent metabolic syndrome. Finally, we discuss the potential for dietary restriction of specific amino acids - or pharmaceuticals which harness these same mechanisms - to promote healthy aging.

Keywords: Amino acids; BCAAs; Diabetes; Obesity; Protein restriction.

Figure 1:

FGF21 is a key mediator of the metabolic effects of protein and amino acid restriction. FGF21 = fibroblast growth factor 21, PCG1α = Peroxisome proliferator-activated receptor-γ coactivator-1α, PPAR-α = Peroxisome proliferator-activated receptor-α, UCP1 = uncoupling protein 1.

Figure 2:

Regulation of mTORC1 by amino acids. AMP = adenosine monophosphate, AMPK = AMP-activated protein kinase, ATP = adenosine triphosphate, mTORC1 = mechanistic target of rapamycin complex 1, Raptor = regulatory-associated protein of mTOR, Rheb = Ras homolog enriched in brain, SAMTOR = S-adenosyl methionine/target of rapamycin, TSC = tuberous sclerosis complex.

Figure 3:

Cross-talk between the mTORC1, GCN2 and FGF21 signaling pathways in the presence and absence of amino acids. AMPK = AMP-activated protein kinase, ATF4 = activating transcription factor 4, eIF2α = eukaryotic initiation factor 2, FGF21 = fibroblast-growth factor 21, GCN2 = general control nonderepressible 2, mTORC1 = mechanistic target of rapamycin complex 1, TSC = tuberous sclerosis complex.