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

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 improvemen...

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Published in:	Cell metabolism Vol. 34; no. 2; pp. 209 - 226.e5
Main Authors:	Green, Cara L, Pak, Heidi H, Richardson, Nicole E, Flores, Victoria, Yu, Deyang, Tomasiewicz, Jay L, Dumas, Sabrina N, Kredell, Katherine, Fan, Jesse W, Kirsh, Charlie, Chaiyakul, Krittisak, Murphy, Michaela E, Babygirija, Reji, Barrett-Wilt, Gregory A, Rabinowitz, Joshua, Ong, Irene M, Jang, Cholsoon, Simcox, Judith, Lamming, Dudley W
Format:	Journal Article
Language:	English
Published:	United States 01-02-2022
Subjects:	Animals Diet, Protein-Restricted Energy Metabolism - genetics Female Fibroblast Growth Factors - metabolism Genetic Background Insulin Resistance - genetics Liver - metabolism Male Mice protein restriction metabolic health UM-HET3 liver multi-omics genetic variation precision dietetics sexual dimorphism FGF21
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS C.L.G., I.M.O., C.J., J.S., and D.W.L. conceived of and designed the experiments. C.L.G., H.H.P., N.E.R., V.F., D.Y., J.L.T., S.N.D., K.K., J.W.F., C.K., K.C., M.E.M., R.B., G.A.B., and C.J. performed the experiments. C.L.G., K.C., I.M.O., C.J., J.S., and D.W.L. analyzed the data. C.L.G., J.R., I.M.O., C.J., J.S., and D.W.L. wrote the manuscript.
ISSN:	1550-4131 1932-7420 1932-7420
DOI:	10.1016/j.cmet.2021.12.018