Trautman Michaela E, Green Cara L, MacArthur Michael R, Chaiyakul Krittisak, Alam Yasmine H, Yeh Chung-Yang, Babygirija Reji, James Isabella, Gilpin Michael, Zelenovskiy Esther, Green Madelyn, Marshall Ryan N, Raskin Alexander, Sonsalla Michelle M, Flores Victoria, Simcox Judith A, Ong Irene M, Malecki Kristen C, Jang Cholsoon, Lamming Dudley W
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Nutrition and Metabolism Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
Mol Metab. 2025 Sep 10:102248. doi: 10.1016/j.molmet.2025.102248.
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.
饮食中的氨基酸组成最近已成为代谢健康的关键调节因子。支链氨基酸异亮氨酸的摄入量与人类体重指数呈正相关，降低饮食中异亮氨酸的水平可迅速改善饮食诱导的肥胖雄性C57BL/6J小鼠的代谢健康。然而，有一些报告称，额外补充支链氨基酸对健康有益。此外，在西式饮食（WD）条件下，性别、遗传背景和饮食异亮氨酸水平之间的相互作用仍未完全了解。在这里，我们发现，尽管影响程度因性别和品系而异，但降低饮食中异亮氨酸的水平可保护两性的C57BL/6J和DBA/2J小鼠免受WD的有害代谢影响，而增加饮食中异亮氨酸的水平则会损害代谢健康的某些方面。尽管所有性别和品系对降低异亮氨酸的反应总体上是积极的，但每个性别和品系的分子反应却高度独特。使用多组学方法，我们确定了对饮食异亮氨酸的核心性别和品系独立分子反应，并确定了与每种表型相关的差异表达肝脏基因、代谢物和脂质的大型簇。有趣的是，小鼠中异亮氨酸减少的代谢作用与成纤维细胞生长因子21（FGF21）无关——我们发现，在人类中，血浆FGF21水平同样与饮食中异亮氨酸的水平无关。最后，对人类国家健康与营养检查调查（NHANES）数据的分析表明，不同食物中的异亮氨酸含量差异很大，健康饮食指数得分较高的个体往往摄入较少的异亮氨酸。我们的结果表明，饮食中异亮氨酸的水平是对WD的代谢和分子反应的潜在调节因子，并暗示降低饮食中的异亮氨酸可能是一种理论上可转化的策略，以防止WD带来的负面代谢后果。
