ArticleCell metabolism2022
Sex and genetic background define the metabolic, physiologic, and molecular response to protein restriction.
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Article in Cell metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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64citing papers in PubMed
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64 citing papers in PubMed, 107 citations in OpenAlex.
- The hallmarks of protein and amino acid restriction in aging and longevity.Cell press blue · 2026Article
- Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.Nature aging · 2026Article
- Female resistance to the metabolic benefits of protein restriction is reversed by ovariectomy in mice.bioRxiv : the preprint server for biology · 2026Article
- FGF21 signals through hindbrain neurons to alter food intake and energy expenditure during dietary protein restriction.Cell reports · 2026Article
- A nutrient-hormone axis pivots an energy trade-off between resting thermogenesis and movement expenditure.Journal of sport and health science · 2026Article
- Dietary restriction in aging and longevity.Nature aging · 2026Review
- The Sixth Annual Symposium of the Midwest Aging Consortium.The journals of gerontology. Series A, Biological sciences and medical sciences · 2026Article
- Low protein-induced-FGF-21 signaling remodels adipose tissue on reduced markers of senescence during aging.GeroScience · 2026Article
- Hepatic FGF21 Deletion Improves Glucose Metabolism, Alters Lipogenic andInternational journal of molecular sciences · 2025Article
- A low-protein diet drives short- and long-term improvements in metabolic health in a mouse model of sleeve gastrectomy.Cell reports. Medicine · 2025Article
- Sex Differences in Associations Between Diet and Metabolic Health in Older Adults: The Roles of Vegetable Protein and Alcohol Intake.Nutrients · 2025Article
- Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice.Molecular metabolism · 2025Article
- Tissue-Specific Effects of Dietary Protein on Cellular Senescence Are Mediated by Branched-Chain Amino Acids.Aging cell · 2025Article
- Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.bioRxiv : the preprint server for biology · 2025Article
- Paternity testing for crab-eating macaques and rhesus macaques using microsatellite markers.Animal models and experimental medicine · 2025Article
- Manipulating dietary protein and amino acids in the common marmoset Callithrix jacchus impacts circulating metabolites and FGF21 levels.Scientific reports · 2025Article
- Brain amino acid sensing for organismal amino acid homeostasis.Open biology · 2025Review
- Dietary macronutrient content and energy intake in the mouse: hedonic or homeostatic override?Obesity (Silver Spring, Md.) · 2025Article
- Protection against APOE4-associated phenotypes with the longevity-promoting intervention 17α-estradiol in middle-aged male mice.Communications medicine · 2025Article
- Dietary sulfur amino acid restriction improves metabolic health by reducing fat mass.Life metabolism · 2025Article
4 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 3 institutions in 1 country.
Cara L GreenDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
Heidi H PakDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Nicole E RichardsonDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
Victoria FloresDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Deyang YuDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Molecular and Environmental Toxicology Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
Jay L TomasiewiczWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
Sabrina N DumasDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
Katherine KredellDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
Jesse W FanDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
Charlie KirshDepartment of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Krittisak ChaiyakulDepartment of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53705, USA.
Michaela E MurphyDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Reji BabygirijaDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Gregory A Barrett-WiltBiotechnology Center, University of Wisconsin-Madison, Madison, WI 53706, USA.
Joshua RabinowitzDepartment of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Irene M OngDepartment of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53705, USA; University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53705, USA; Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USA.
Cholsoon JangDepartment of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
Judith SimcoxInterdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Dudley W LammingDepartment of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA; Molecular and Environmental Toxicology Program, University of Wisconsin-Madison, Madison, WI 53706, USA; Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706, USA; University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI 53705, USA. Electronic address: dlamming@medicine.wisc.edu.
University of Wisconsin–Madison · USPrinceton University · USWilliam S. Middleton Memorial Veterans Hospital · US
Funding
UW COMPREHENSIVE CANCER CENTER SUPPORTP30CA014520 · NCI · UNIVERSITY OF WISCONSIN-MADISON · PI Christian Capitini · 1985 to 2026
$142.6MVIRAL VECTOR COREP30DK019525 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI Patrick Seale · 1986 to 2026
$48.3MWU P&FP30DK020579 · NIDDK · WASHINGTON UNIVERSITY · PI Clay F. Semenkovich · 2013 to 2026
$27.1MProject 3: Modulation of the head and neck tumor immune microenvironment by targeting the TAM family of receptorsP50CA278595 · NCI · UNIVERSITY OF WISCONSIN-MADISON · PI Zachary Scott Morris · 2022 to 2026
$12.5MProject 4: Role of Receptor Tyrosine Kinase AXL in HNSCC Therapy ResistanceP50DE026787 · NIDCR · UNIVERSITY OF WISCONSIN-MADISON · PI HARARI, PAUL M · 2016 to 2020
$10.8MBiology of Aging and Age-Related Diseases Training GrantT32AG000213 · NIA · UNIVERSITY OF WISCONSIN-MADISON · PI Rozalyn M. Anderson, Sanjay Asthana · 1991 to 2026
$9.9MTRAINING IN NUTRITIONT32DK007665 · NIDDK · UNIVERSITY OF WISCONSIN-MADISON · PI GUY E GROBLEWSKI, Chi- Liang Eric Yen · 1993 to 2026
$9.2MMetabolism in Action: Quantitative Fluxes in MammalsDP1DK113643 · NIDDK · PRINCETON UNIVERSITY · PI RABINOWITZ, JOSHUA D · 2016 to 2020
$5.7MThe regulation of health and longevity by branched-chain amino acidsR01AG056771 · NIA · UNIVERSITY OF WISCONSIN-MADISON · PI Dudley William Lamming · 2018 to 2026
$3.1MUniversity of Wisconsin Building Interdisciplinary Research Careers in Women's Health (BIRCWH) Scholars ProgramK12HD101368 · NICHD · UNIVERSITY OF WISCONSIN-MADISON · PI BARROILHET, LISA M, BURNSIDE, ELIZABETH S · 2020 to 2023
$2.9MUniversity of Wisconsin Building Interdisciplinary Research Careers in Women's Health (BIRCWH) Scholars ProgramK12AR084227 · NIAMS · UNIVERSITY OF WISCONSIN-MADISON · PI ELIZABETH S BURNSIDE, Lisa M Barroilhet · 2023 to 2026
$2.5MThe regulation of health and longevity by branched-chain amino acidsRF1AG056771 · NIA · UNIVERSITY OF WISCONSIN-MADISON · PI LAMMING, DUDLEY WILLIAM · 2023 to 2023
$2.1MBLRD VA I01 BX004031NCI NIH HHS P30 CA014520NCI NIH HHS P50 CA278595NIAMS NIH HHS K12 AR084227NIA NIH HHS F31 AG066311NIA NIH HHS R01 AG056771NIA NIH HHS R01 AG062328NIA NIH HHS R21 AG061635NIA NIH HHS R56 AG056771NIA NIH HHS RF1 AG056771NIA NIH HHS T32 AG000213NICHD NIH HHS K12 HD101368NIDCR NIH HHS P50 DE026787NIDDK NIH HHS DP1 DK113643NIDDK NIH HHS P30 DK019525NIDDK NIH HHS P30 DK020579NIDDK NIH HHS R01 DK125859NIDDK NIH HHS T32 DK007665
Abstract
Low-protein diets promote metabolic health in humans and rodents. Despite evidence that sex and genetic background are key factors in the response to diet, most protein intake studies examine only a single strain and sex of mice. Using multiple strains and both sexes of mice, we find that improvements in metabolic health in response to reduced dietary protein strongly depend on sex and strain. While some phenotypes were conserved across strains and sexes, including increased glucose tolerance and energy expenditure, we observed high variability in adiposity, insulin sensitivity, and circulating hormones. Using a multi-omics approach, we identified mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype, providing molecular insight into the differential response to protein restriction. Our results highlight the importance of sex and genetic background in the response to dietary protein level, and the potential importance of a personalized medicine approach to dietary interventions.
Indexed as
Diet, Protein-RestrictedInsulin ResistanceAnimalsEnergy MetabolismFemaleFibroblast Growth FactorsGenetic BackgroundLiverMaleMiceFibroblast Growth FactorsFGF21genetic variationlivermetabolic healthmulti-omicsprecision dieteticsprotein restrictionsexual dimorphismUM-HET3
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