@article{5c249e16329b4de497f9611a2ca07960,
title = "Sex and genetic background define the metabolic, physiologic, and molecular response to protein restriction",
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.",
keywords = "FGF21, UM-HET3, genetic variation, liver, metabolic health, multi-omics, precision dietetics, protein restriction, sexual dimorphism",
author = "Green, {Cara L.} and Pak, {Heidi H.} and Richardson, {Nicole E.} and Victoria Flores and Deyang Yu and Tomasiewicz, {Jay L.} and Dumas, {Sabrina N.} and Katherine Kredell and Fan, {Jesse W.} and Charlie Kirsh and Krittisak Chaiyakul and Murphy, {Michaela E.} and Reji Babygirija and Barrett-Wilt, {Gregory A.} and Joshua Rabinowitz and Ong, {Irene M.} and Cholsoon Jang and Judith Simcox and Lamming, {Dudley W.}",
note = "Funding Information: We thank all members of the Lamming lab for their feedback, R. Jain for assistance with lipidomics, Dr. Herfel (Envigo) for assistance with diets, and Drs. Jay Mitchell and Michael MacArthur for insightful discussions. The Lamming lab is supported in part by the NIA ( AG056771 , AG062328 , and AG061635 ), the NIDDK ( DK125859 ), and startup funds from UW-Madison . C.L.G. is supported in part by Dalio Philanthropies and is a Glenn Foundation for Medical Research Postdoctoral Fellow. H.H.P. is supported in part by F31AG066311 . C.J. was a postdoctoral fellow of the American Diabetes Association ( 1-17-PDF-076 ). N.E.R. was supported in part by training grant T32AG000213 . D.Y. is supported in part by a fellowship from the American Heart Association ( 17PRE33410983 ). M.E.M. is supported in part by a Supplement to Promote Diversity in Health-Related Research ( R01AG062328-03S1 ). R.B. is supported in part by training grant T32DK007665 . J.R. is supported in part by DP1DK113643 and metabolomics work supported by P30DK019525 . Lipidomics work was supported by a pilot grant to J.S. from the Diabetes Research Center at Washington University , P30DK020579 , and a UW BIRCWH Scholars Program award to J.S. ( K12HD101368 ). I.O. is supported by UWCCC support grant P30 CA014520 and Wisconsin Head and Neck Cancer SPORE CEP P50DE026787 . Support was also provided by the UW-Madison OVCRGE with funding from the Wisconsin Alumni Research Foundation . This work was supported in part by the US 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. Funding Information: We thank all members of the Lamming lab for their feedback, R. Jain for assistance with lipidomics, Dr. Herfel (Envigo) for assistance with diets, and Drs. Jay Mitchell and Michael MacArthur for insightful discussions. The Lamming lab is supported in part by the NIA (AG056771, AG062328, and AG061635), the NIDDK (DK125859), and startup funds from UW-Madison. C.L.G. is supported in part by Dalio Philanthropies and is a Glenn Foundation for Medical Research Postdoctoral Fellow. H.H.P. is supported in part by F31AG066311. C.J. was a postdoctoral fellow of the American Diabetes Association (1-17-PDF-076). N.E.R. was supported in part by training grant T32AG000213. D.Y. is supported in part by a fellowship from the American Heart Association (17PRE33410983). M.E.M. is supported in part by a Supplement to Promote Diversity in Health-Related Research (R01AG062328-03S1). R.B. is supported in part by training grant T32DK007665. J.R. is supported in part by DP1DK113643 and metabolomics work supported by P30DK019525. Lipidomics work was supported by a pilot grant to J.S. from the Diabetes Research Center at Washington University, P30DK020579, and a UW BIRCWH Scholars Program award to J.S. (K12HD101368). I.O. is supported by UWCCC support grant P30 CA014520 and Wisconsin Head and Neck Cancer SPORE CEP P50DE026787. Support was also provided by the UW-Madison OVCRGE with funding from the Wisconsin Alumni Research Foundation. This work was supported in part by the US 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. 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. D.W.L. 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. Publisher Copyright: {\textcopyright} 2021",
year = "2022",
month = feb,
day = "1",
doi = "10.1016/j.cmet.2021.12.018",
language = "English (US)",
volume = "34",
pages = "209--226.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "2",
}