The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, the study demonstrates that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis.

Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, the study demonstrates that variation in dietary isoleucine levels helps explain body mass index differences in humans. The results of the study reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.

The recent studies discussed here suggest that dietary restriction of specific branched-chain amino acids (BCAAs), specifically isoleucine (Ile), has distinct physiological and metabolic effects in mice. Reducing dietary Ile, and to a lesser extent valine (Val), promotes glucose tolerance and reduces adiposity in lean mice, whereas restriction of leucine (Leu) tended to have negative effects. Furthermore, dietary restriction of Ile is necessary for the full physiological and metabolic effects of a low protein (LP) diet and is necessary and sufficient to restore metabolic health to diet-induced obese (DIO) mice.

The mechanisms underlying the metabolic benefits of a reduced Ile diet are not fully understood but are likely to involve multiple physiological and molecular mechanisms. The improved glucose homeostasis of low Ile-fed mice is partly due to improved hepatic insulin sensitivity, but it does not require suppression of hepatic mammalian target of rapamycin complex 1 (mTORC1) signaling or activation of hepatic general control nonderepressible 2 (GCN2) signaling. The reduction of dietary Ile by 67% induces FGF21 transcription in multiple tissues and raises blood levels of FGF21, which is required for a reduced Ile diet to increase food consumption and plays a role in the increased energy expenditure of low Ile-fed mice.

The distinct effects of reduction of Leu from that of Ile and Val reduction may be due to altered catabolism of Leu and Val in low Ile-fed mice. Increased catabolism of BCAAs, particularly Leu and Val, may be one possible mechanism underlying the metabolic benefits of low Ile diets. Increased levels of acetyl-CoA and acetoacetate, which are in part Leu derived, would then be available to support increased ketogenesis and lipogenesis, and may contribute to the metabolic response to reduced dietary Ile.

Further research is required to fully define the mechanisms by which dietary Ile regulates the expression of Fgf21 and programs metabolism, and to determine the role of FGF21 in the effect of dietary Ile on energy balance. Elucidating both the FGF21-dependent and FGF21-independent mechanisms by which a reduction in dietary Ile or Val promotes leanness without calorie restriction will be an important area of future study.

Any thoughts on how to lower isoleucine and valine but not leucine?