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

Michaela E Trautman; Cara L Green; Michael R MacArthur; Krittisak Chaiyakul; Yasmine H Alam; Chung-Yang Yeh; Reji Babygirija; Isabella James; Michael Gilpin; Esther Zelenovskiy; Madelyn Green; Ryan N Marshall; Alexander Raskin; Michelle M Sonsalla; Victoria Flores; Judith A Simcox; Irene M Ong; Kristen C Malecki; Cholsoon Jang; Dudley W Lamming

doi:10.1016/j.molmet.2025.102248

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

Michaela E Trautman, Cara L Green, Michael R MacArthur, Krittisak Chaiyakul, Yasmine H Alam, Chung-Yang Yeh, Reji Babygirija, Isabella James, Michael Gilpin, Esther Zelenovskiy, Madelyn Green, Ryan N Marshall, Alexander Raskin, Michelle M Sonsalla, Victoria Flores, Judith A Simcox, Irene M Ong, Kristen C Malecki, Cholsoon Jang, Dudley W Lamming

Department for Health

Research output: Contribution to journal › Article › peer-review

2 Citations (SciVal)

Abstract

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.

Original language	English
Article number	102248
Journal	Molecular Metabolism
Volume	101
Early online date	10 Sept 2025
DOIs	https://doi.org/10.1016/j.molmet.2025.102248
Publication status	Published - 30 Nov 2025

Data Availability Statement

RNA-sequencing data have been deposited with the Gene Expression Omnibus and are available under accession number GSE271655. Metabolomics data has been deposited with MetaboLights under identifier MTBLS11294; lipidomic data has been deposited with MassIVE under identifier MSV000096669. Other source data is attached as supporting information files.

Acknowledgements

The Lamming lab is supported in part by the NIA (AG056771, AG081482, AG084156 and AG085898, AG094153), the NIDDK (DK125859), the Wisconsin Partnership Program, and startup funds from UW-Madison. M.E.T. is supported by K00AG083290. CLG was supported in part by Dalio Philanthropies, a Glenn Foundation Postdoctoral Fellowship, and by Hevolution Foundation award HF-AGE AGE-009. RB is supported by F31AG081115. C-YY was supported by T32AG000213, F32AG077916, and K99AG084921. MMS was supported in part by a Supplement to Promote Diversity in Health-Related Research RF1AG056771-06S1. JS is supported by the NIDDK (R01DK133479., P30DK020579), Hatch Grant (WIS04000-1024796); and JDRF (JDRF201309442). RM is supported by a Glenn Foundation Postdoctoral Fellowship. JS is a HHMI Freeman Hrabowski Scholar and is an American Federation for Aging Research grant recipient. CJ is supported in part by the NIAAA (R01AA029124). IO was supported by UWCCC Support Grant P30 CA014520 and Wisconsin Head and Neck Cancer SPORE CEP P50DE026787. WAR was supported by U54DK104310 and R01DK131175. Support was provided by the UW-Madison OVCRGE with funding from the Wisconsin Alumni Research Foundation. The authors used the UW-Madison Biotechnology Center Gene Expression Center (RRID: SCR_017757). The Survey of the Health of Wisconsin was funded by the Wisconsin Partnership Program. JAS, IMO, and DWL D.W.L. are members of the Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, P30 AG092586. The Lamming lab was supported in part by the U.S. Department of Veterans Affairs (I01-BX004031), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the United States Government. Figure 1/panel A Created with BioRender.com released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license".

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Animals
Isoleucine/metabolism
Male
Mice
Female
Mice, Inbred C57BL
Diet, Western/adverse effects
Mice, Inbred DBA
Obesity/metabolism
Liver/metabolism
Amino Acids, Branched-Chain/metabolism
Humans

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Cite this

Trautman, M. E., Green, C. L., MacArthur, M. R., Chaiyakul, K., Alam, Y. H., Yeh, C.-Y., Babygirija, R., James, I., Gilpin, M., Zelenovskiy, E., Green, M., Marshall, R. N., Raskin, A., Sonsalla, M. M., Flores, V., Simcox, J. A., Ong, I. M., Malecki, K. C., Jang, C., & Lamming, D. W. (2025). Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice. Molecular Metabolism, 101, Article 102248. https://doi.org/10.1016/j.molmet.2025.102248

Trautman, ME, Green, CL, MacArthur, MR, Chaiyakul, K, Alam, YH, Yeh, C-Y, Babygirija, R, James, I, Gilpin, M, Zelenovskiy, E, Green, M, Marshall, RN, Raskin, A, Sonsalla, MM, Flores, V, Simcox, JA, Ong, IM, Malecki, KC, Jang, C & Lamming, DW 2025, 'Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice', Molecular Metabolism, vol. 101, 102248. https://doi.org/10.1016/j.molmet.2025.102248

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abstract = "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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AU - Alam, Yasmine H

AU - Yeh, Chung-Yang

AU - Babygirija, Reji

AU - James, Isabella

AU - Gilpin, Michael

AU - Zelenovskiy, Esther

AU - Green, Madelyn

AU - Marshall, Ryan N

AU - Raskin, Alexander

AU - Sonsalla, Michelle M

AU - Flores, Victoria

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JF - Molecular Metabolism

M1 - 102248

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

Abstract

Data Availability Statement

Acknowledgements

UN SDGs

Keywords

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