Dietary isoleucine content defines the metabolic and molecular response to a Western diet.

Autor:	Trautman ME; 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., Green CL; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA., MacArthur MR; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08540, USA., Chaiyakul K; Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, WI 53705, USA., Alam YH; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Yeh CY; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA., Babygirija R; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA.; Cell and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA., James I; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA., Gilpin M; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA., Zelenovskiy E; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA., Green M; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA., Marshall RN; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA., Sonsalla MM; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA.; Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53706, USA., Flores V; 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., Simcox JA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.; Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53706, USA., Ong IM; Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, WI 53705, USA., Malecki KC; Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA., Jang C; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA., Lamming DW; 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.; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ 08540, USA.; Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.; University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53705, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 03. Date of Electronic Publication: 2024 Jun 03.
DOI:	10.1101/2024.05.30.596340
Abstrakt:	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, it is unknown how sex, strain, and dietary isoleucine intake may interact to impact the response to a Western Diet (WD). 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, we find that foods contain a range of isoleucine levels, and that consumption of dietary isoleucine is lower in humans with healthy eating habits. Our results demonstrate that the dietary level of isoleucine is critical in the metabolic and molecular response to a WD, and suggest that lowering dietary levels of isoleucine may be an innovative and translatable strategy to protect from the negative metabolic consequences of a WD. Competing Interests: DECLARATION OF INTERESTS DWL has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases.
Databáze:	MEDLINE
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