Dietary branched chain amino acids and metabolic health: when less is more

Within obesity research it is almost axiomatic that the consumption of adequate protein is healthy. A large body of work suggests that high protein diets reduce food intake, while maintaining protein intake but reducing caloric intake promotes fat loss while sustaining lean mass. Yet evidence is also accumulating to suggest that excess protein intake negatively impacts health, and that the restriction of dietary protein triggers beneficial metabolic effects. This body of work derives in part from efforts in the ageing field to define the mechanisms through which dietary restriction extends lifespan. In this issue of The Journal of Physiology, Cummings et al. (2018) provide compelling evidence that the restriction of branched chain amino acid (BCAA) intake is sufficient to restore metabolic health in obese mice. Although it has long been known that BCAAs are elevated in settings of obesity (Felig et al. 1974), work by Newgard and colleagues in 2009 rekindled interest in this field by demonstrating that elevated BCAAs contribute to a 'metabolic signature' predicting insulin resistance in obese humans (Newgard et al. 2009). Furthermore, supplementing high-fat-fed animals with excess BCAAs reduced food intake and body weight but failed to improve glucose tolerance. This negative effect of excess BCAAs is consistent with more recent work by several groups suggesting that restricting dietary protein intake improves glucose tolerance and other metabolic endpoints. Cummings et al. build on their prior work (Fontana et al. 2016) by testing the impact of BCAA restriction in mice with established obesity. The key question is whether reducing dietary BCAA intake alone is sufficient to improve glucose homeostasis in obese mice, and whether this effect rivals the beneficial effects produced by the restriction of dietary protein (all amino acids). This question is first tested by transitioning mice made obese with a high fat 'Western diet' (WD) to a low fat, low BCAA diet. Not surprisingly, swapping mice from WD to low fat diet reduced adiposity and improved glucose homeostasis. However, the low BCAA diet was even more effective, producing a larger weight loss and improvement in glucose tolerance than low fat alone. The BCAA restriction also largely replicated the effect of a diet that was low in all AAs. While this study suggested that BCAA restriction exerts beneficial effects, the authors recognized the weakness inherent in simultaneously manipulating energy density, macronutrient content and amino acid ratios. Therefore, a second study was designed in which mice were made obese by 12 weeks of WD exposure and then swapped to a WD specifically restricting BCAAs. In this context the restriction of dietary BCAAs significantly decreased body weight and adiposity, increased energy expenditure, and improved glucose tolerance and insulin sensitivity. BCAA restriction also largely recapitulated the metabolic effects induced by the restriction of all amino acids. These data provide compelling evidence that restricting BCAAs is sufficient to restore metabolic health in the context of continuous WD exposure. The observation that restriction of BCAAs produces metabolic benefits that are comparable to the restriction of all AAs (dietary protein restriction) leads to the logical question of whether the beneficial effect of low protein diets are mediated by BCAAs. While the current data are consistent with this conclusion, there are reasons to be cautious. Cummings et al. demonstrate that BCAA restriction is sufficient to trigger metabolic improvements, but do not test whether BCAA restriction is necessary for the effects of protein restriction. Answering this question requires restricting dietary protein but restoring BCAAs to control levels. Interestingly, a recent study by Maida et al. (2017) used this design to suggest that the normalizing BCAA intake only attenuates the metabolic effect of protein restriction in lean mice and has no effect in genetically obese NZO mice. Taken together, the work of Cummings et al. and Maida et al. suggest that although BCAA restriction reproduces aspects of the metabolic response to general protein restriction, BCAA restriction does not functionally account for all the effects of protein restriction. It should be noted that the metabolic effects of BCAA restriction and protein (all AA) restriction are similar, but not interchangeable (Fontana et al. 2016; Cummings et al. 2018). While Cummings et al. provide compelling evidence that BCAA restriction influences metabolic endpoints, the report does not identify the mechanistic pathways that drive these improvements. For instance, BCAAs and leucine in particular are known to stimulate mechanistic target of rapamycin (mTOR) signalling, and mTOR has been linked to the regulation of insulin sensitivity. Restricting or supplementing leucine alone would have further complemented their prior work (Fontana et al. 2016) by delineating whether leucine is the primary mediator of the BCAA effect. Finally, a growing body of work implicates the metabolic hormone fibroblast growth factor 21 (FGF21) as a key mediator of dietary protein restriction (Laeger et al. 2014), but its contribution to the effect of BCAA restriction remains unclear. Cummings et al. suggest that restriction of BCAAs has inconsistent effects on FGF21, which was increased after 12 days on diet but not after 12 weeks. This temporal variability in the FGF21 response is also associated with temporal variability in other endpoints, such as food intake and energy expenditure. Therefore, when and how BCAA restriction influences metabolism, particularly glucose homeostasis, remain unclear. The report by Cummings et al. provides strong evidence that reducing BCAA intake restores metabolic health in obese rodents, thereby adding to a growing body of work suggesting that restriction of dietary protein or select amino acids promotes beneficial metabolic adaptations. Future work is necessary to define how these various dietary interventions produce these effects, the extent to which the underlying mechanisms are similar or divergent, and finally whether these beneficial effects can be translated to humans. None declared. Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.