Abstract
Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 905-922.e6 |
| Journal | Cell Metabolism |
| Volume | 33 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 4 2021 |
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Physiology
- Cell Biology
Keywords
- FGF21
- GCN2
- body mass index
- branched-chain amino acids
- diabetes
- insulin resistance
- isoleucine
- mTORC1
- obesity
- valine
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Cell Metabolism, Vol. 33, No. 5, 04.05.2021, p. 905-922.e6.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine
AU - Yu, Deyang
AU - Richardson, Nicole E.
AU - Green, Cara L.
AU - Spicer, Alexandra B.
AU - Murphy, Michaela E.
AU - Flores, Victoria
AU - Jang, Cholsoon
AU - Kasza, Ildiko
AU - Nikodemova, Maria
AU - Wakai, Matthew H.
AU - Tomasiewicz, Jay L.
AU - Yang, Shany E.
AU - Miller, Blake R.
AU - Pak, Heidi H.
AU - Brinkman, Jacqueline A.
AU - Rojas, Jennifer M.
AU - Quinn, William J.
AU - Cheng, Eunhae P.
AU - Konon, Elizabeth N.
AU - Haider, Lexington R.
AU - Finke, Megan
AU - Sonsalla, Michelle
AU - Alexander, Caroline M.
AU - Rabinowitz, Joshua D.
AU - Baur, Joseph A.
AU - Malecki, Kristen C.
AU - Lamming, Dudley W.
N1 - Funding Information: We would like to thank Dr. Dawn Davis and Dr. Vincent Cryns for their valuable insights and comments. We thank Dr. Tina Herfel (Envigo) for assistance with diet formulation. The MANLAC2 (10F8) antibody was developed by G.E. Morris and was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH, and maintained at the University of Iowa, Department of Biology, Iowa City, IA 52242. The work was supported in part by the NIH /NIA ( AG056771 , AG062328 , and AG061635 to D.W.L.), the NIH/ NIGMS ( GM113142 to C.M.A.), the NIH/ NIAMS ( P30 AR066524 Pilot Award to I.K.), the NIH/ NIDDK ( DP1DK113643 to J.D.R.), a Glenn Foundation Award for Research in the Biological Mechanisms of Aging to D.W.L., and startup funds from the UW-Madison School of Medicine and Public Health and Department of Medicine to D.W.L. Support for this research was provided by the UW-Madison Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation . The Survey of the Health of Wisconsin is funded by the Wisconsin Partnership Program . This research was conducted while D.W.L. was an AFAR Research Grant recipient from the American Federation for Aging Research . D.Y. was supported in part by a fellowship from the American Heart Association ( 17PRE33410983 ). N.E.R. was supported in part by a training grant from the UW Institute on Aging (NIA T32 AG000213 ). C.L.G. was supported in part by a grant from Dalio Philanthropies and is supported by a Glenn Foundation for Medical Research Postdoctoral Fellowship in Aging Research. V.F. and M.E.M. were supported in part by Research Supplements to Promote Diversity in Health-Related Research ( R01 AG056771-01A1S1 and R01AG062328-03S1 ). H.H.P. was supported in part by a NIA F31 predoctoral fellowship ( AG066311 ). I.K. was supported in part by McArdle Departmental Funds . C.J. was supported by the American Diabetes Association ( 1-17-PDF-076 ). Metabolomics work was supported by Diabetes Research Center grant P30 DK019525 . The UW Carbone Cancer Center (UWCCC) Experimental Pathology Laboratory is supported by P30 CA014520 from the NIH/ NCI . Clamp studies were performed in the Rodent Metabolic Phenotyping Core of the University of Pennsylvania Diabetes Research Center ( P30 DK19525 ); this award also supported in part the metabolomics analysis. This work was supported in part by the U.S. 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 would like to thank Dr. Dawn Davis and Dr. Vincent Cryns for their valuable insights and comments. We thank Dr. Tina Herfel (Envigo) for assistance with diet formulation. The MANLAC2 (10F8) antibody was developed by G.E. Morris and was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH, and maintained at the University of Iowa, Department of Biology, Iowa City, IA 52242. The work was supported in part by the NIH/NIA (AG056771, AG062328, and AG061635 to D.W.L.), the NIH/NIGMS (GM113142 to C.M.A.), the NIH/NIAMS (P30 AR066524 Pilot Award to I.K.), the NIH/NIDDK (DP1DK113643 to J.D.R.), a Glenn Foundation Award for Research in the Biological Mechanisms of Aging to D.W.L. and startup funds from the UW-Madison School of Medicine and Public Health and Department of Medicine to D.W.L. Support for this research was provided by the UW-Madison Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation. The Survey of the Health of Wisconsin is funded by the Wisconsin Partnership Program. This research was conducted while D.W.L. was an AFAR Research Grant recipient from the American Federation for Aging Research. D.Y. was supported in part by a fellowship from the American Heart Association (17PRE33410983). N.E.R. was supported in part by a training grant from the UW Institute on Aging (NIA T32 AG000213). C.L.G. was supported in part by a grant from Dalio Philanthropies and is supported by a Glenn Foundation for Medical Research Postdoctoral Fellowship in Aging Research. V.F. and M.E.M. were supported in part by Research Supplements to Promote Diversity in Health-Related Research (R01 AG056771-01A1S1 and R01AG062328-03S1). H.H.P. was supported in part by a NIA F31 predoctoral fellowship (AG066311). I.K. was supported in part by McArdle Departmental Funds. C.J. was supported by the American Diabetes Association (1-17-PDF-076). Metabolomics work was supported by Diabetes Research Center grant P30 DK019525. The UW Carbone Cancer Center (UWCCC) Experimental Pathology Laboratory is supported by P30 CA014520 from the NIH/NCI. Clamp studies were performed in the Rodent Metabolic Phenotyping Core of the University of Pennsylvania Diabetes Research Center (P30 DK19525); this award also supported in part the metabolomics analysis. This work was supported in part by the U.S. 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. D.Y. N.E.R. C.J. I.K. M.N. J.M.R. C.M.A. J.D.R. J.A. Baur, K.C.M. and D.W.L. conceived of and designed the experiments. D.Y. N.E.R. C.L.G. A.B.S. M.E.M. V.F. C.J. I.K. M.H.W. J.L.T. S.E.Y. B.R.M. H.H.P. J.A. Brinkman, W.J.Q. E.P.C. E.N.K. L.R.H. M.F. and M.S. performed the experiments. D.Y. N.E.R. C.L.G. A.B.S. M.E.M. V.F. C.J. I.K. M.N. C.M.A. J.D.R. J.A. Baur, K.C.M. and D.W.L. analyzed the data. D.Y. N.E.R. C.L.G. A.B.S. J.M.R. C.M.A. J.D.R. J.A. Baur, K.C.M. 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. UW-Madison has applied for a patent based in part on the findings reported here, for which N.E.R. and D.W.L. are inventors. Publisher Copyright: © 2021
PY - 2021/5/4
Y1 - 2021/5/4
N2 - Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
AB - Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
KW - FGF21
KW - GCN2
KW - body mass index
KW - branched-chain amino acids
KW - diabetes
KW - insulin resistance
KW - isoleucine
KW - mTORC1
KW - obesity
KW - valine
UR - http://www.scopus.com/inward/record.url?scp=85104907585&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104907585&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2021.03.025
DO - 10.1016/j.cmet.2021.03.025
M3 - Article
C2 - 33887198
AN - SCOPUS:85104907585
SN - 1550-4131
VL - 33
SP - 905-922.e6
JO - Cell Metabolism
JF - Cell Metabolism
IS - 5
ER -