Health Benefits of Low Protein Diets is all About Isoleucine

Low-protein diets have been shown to exert metabolic and health benefits such as reducing weight and the risk for the metabolic syndrome and type 2 diabetes. Indeed, prospective and retrospective cohort analyses indicates that consumption of dietary protein, particularly from animal sources, increases ones overall risk of mortality.

Some studies have shown that the observed benefits of a low protein diet can be achieved simply by reducing the amount of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine.

A recent study published in the prestigious journal, Cell Metabolism, shows that the negative health consequences associated with BCAA consumption are associated with valine and isoleucine and that reduced isoleucine intake in particular is required in order to observe the health benefits of low-protein diets.

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

Although these studies were carried out in laboratory mice the findings are relevant to humans given that nearly all of the health benefits associated with diets such as low protein or plant-based versus animal based that have been demonstrated in mice have been recapitulated in humans.

The diets utilized in this study were isocaloric meaning that even though a particular BCAA was reduced the total amount of calories consumed by the animals was identical across all the various diets. In addition, each diet had the same level of fats. The percentage of calories from total amino acids was proportionally adjusted by the amount of non-essential amino acids in each diet. The various diets were low leucine, low isoleucine, low valine, or low all three BCAA.

The major finding in this study is that a diet low in isoleucine results in a reprogramming of the metabolic processes in both the liver and adipose tissue resulting in increased hepatic insulin sensitivity and ketogenesis and increased overall energy expenditure. Although valine restriction showed beneficial effects in the liver and adipose tissue these effects were modest in comparison to isoleucine. Leucine restriction had no effect on liver and adipose tissue metabolism.

The animal eating the low isoleucine and low all three BCAA diets had significantly improved glucose tolerance when compared to the other diets. However, there were no significant differences in glucose-stimulated insulin secretion between the four different diets.

Interestingly the animals consuming the low isoleucine or low all three BCAA diet exhibited increased food consumption when normalized by body weight but they gained less weight, fat mass, and lean mass compared to the other diets. In addition, the low isoleucine consuming animals maintained the lowest weight of all the diet groups. The responses of the liver to insulin were greatest in the low isoleucine consuming animals.

Although there has been reported metabolic benefits associated with leucine restriction, this study found no significant benefit and speculated that this was due to differences in overall leucine content in different diet formulations between various studies.

Using both metabolomics and transcriptomics techniques these investigators found that the low isoleucine diet resulted in differences in the expression of 184 genes in the liver of fasting animals and differences in 255 gene in the liver following re-feeding. The processes that were related to these changes in gene expression included lipid, carbohydrate, and amino acid metabolism.

The effects of isoleucine restriction were primarily the result of modifications in the express of the FGF21 gene. FGF21 is a member of the large fibroblast growth factor (FGF) family of proteins, many of which, as the name implies, function as growth factors. This is significant given that many lines of investigation have demonstrated that FGF21 promotes hepatic insulin

sensitivity, regulates energy homeostasis, and increases hepatic ketogenesis. Of significance to humans is the fact that elevated FGF21 is associated with reduced BCAA diets fed to diabetic humans. As well as the liver, the low isoleucine diet increased the expression of the FGF21 gene in adipose tissue, and skeletal muscle.

Correlation studies demonstrate that the level of isoleucine in the diet of humans is associated

with altered metabolic health. An increase in the consumption of isoleucine, relative to total protein, of as little as a single percentage is associated with a 2.46 unit increase in BMI. When proper adjustment were made for the same factors it was found that the intake of leucine and valine were not significantly associated with BMI. These results suggest that dietary protein quality, especially as it relates to the amount of isoleucine, may be an important regulator of metabolic health in humans.

TAKE HOME: It may be useful, in the context of attaining a healthy dietary lifestyle, to consider what type of protein one is consuming and even more importantly, what is the amino acid composition of that protein.