Sex and genetic background define the metabolic, physiologic, and molecular response to protein restriction

Cara L. Green, Heidi H. Pak, Nicole E. Richardson, Victoria Flores, Deyang Yu, Jay L. Tomasiewicz, Sabrina N. Dumas, Katherine Kredell, Jesse W. Fan, Charlie Kirsh, Krittisak Chaiyakul, Michaela E. Murphy, Reji Babygirija, Gregory A. Barrett-Wilt, Joshua Rabinowitz, Irene M. Ong, Cholsoon Jang, Judith Simcox, Dudley W. Lamming

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)209-226.e5
JournalCell Metabolism
Issue number2
StatePublished - Feb 1 2022

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Physiology
  • Cell Biology


  • FGF21
  • UM-HET3
  • genetic variation
  • liver
  • metabolic health
  • multi-omics
  • precision dietetics
  • protein restriction
  • sexual dimorphism


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