Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice

Sep 12, 2025Molecular metabolism

Dietary isoleucine levels change how mice respond metabolically and molecularly to a Western diet

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Abstract

Reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice from the negative metabolic effects of a Western Diet.

Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans.
While reducing isoleucine improves metabolic health in diet-induced obese male mice, increasing its levels impairs metabolic function.
The molecular response to dietary isoleucine varies by sex and genetic background but reveals a core response independent of these factors.
Differentially expressed genes, metabolites, and lipids are clustered based on the dietary isoleucine levels and phenotype in mice.
In humans, plasma FGF21 levels do not correlate with dietary isoleucine intake.
Analysis of human dietary data indicates that those with higher Healthy Eating Index scores generally consume less isoleucine.

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The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, there are some reports that dietary supplementation with extra BCAAs has health benefits. Further, the interactions between sex, genetic background, and dietary isoleucine levels in response to a Western Diet (WD) remain incompletely understood. Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans, plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, an analysis of human NHANES data shows that isoleucine content varies widely across foods, and that individuals with higher Healthy Eating Index scores tend to consume lower amounts of isoleucine. Our results suggest that the dietary level of isoleucine is a potential mediator of the metabolic and molecular response to a WD, and imply that reducing dietary isoleucine may represent a theoretically translatable strategy to protect from the negative metabolic consequences of a WD.

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Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice

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