@article{f252069a087b4c82996d2defdcc2b566,
title = "Gut Microbe-Targeted Choline Trimethylamine Lyase Inhibition Improves Obesity Via Rewiring of Host Circadian Rhythms",
abstract = "Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lepob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics.",
keywords = "Circadian, Insulin resistance, Microbiome, Obesity",
author = "Schugar, {Rebecca C.} and Gliniak, {Christy M.} and Osborn, {Lucas J.} and William Massey and Naseer Sangwan and Anthony Horak and Rakhee Banerjee and Danny Orabi and Helsley, {Robert N.} and Brown, {Amanda L.} and Amy Burrows and Chelsea Finney and Fung, {Kevin K.} and Allen, {Frederick M.} and Daniel Ferguson and Gromovsky, {Anthony D.} and Chase Neumann and Kendall Cook and Amy McMillan and Buffa, {Jennifer A.} and Anderson, {James T.} and Margarete Mehrabian and Maryam Goudarzi and Belinda Willard and Mak, {Tytus D.} and Armstrong, {Andrew R.} and Garth Swanson and Ali Keshavarzian and Garcia-Garcia, {Jose Carlos} and Zeneng Wang and Lusis, {Aldons J.} and Hazen, {Stanley L.} and Brown, {J. Mark}",
note = "Funding Information: This work was supported by National Institutes of Health grants R01 HL120679 (J.M.B.), P01 Funding Information: This work was supported by National Institutes of Health grants R01 HL120679 (J.M.B.), P01 HL147823 (J.M.B., S.L.H.), P50 AA024333 (J.M.B), U01 AA026938 (J.M.B.), R01 DK130227 (J.M.B.), P50 CA150964 (J.M.B.), R01 HL103866 (S.L.H.), R01 HL147883 (A.J.L.), R01 HL144651 (A.J.L. and Z.W.), R01 HL130819 (Z.W.), F32 DK122623 (C.M.G.), T32 DK007307 (C.M.G.), a Leducq Transatlantic Networks of Excellence Award (S.L.H.), and the American Heart Association (Postdoctoral Fellowships 17POST3285000 to R.N.H and 15POST2535000 to R.C.S). Development of some of the mass spectrometry methods reported here were supported by generous pilot grants from the Clinical and Translational Science Collaborative of Cleveland (4UL1TR000439) from the National Center for Advancing Translational Sciences (NCATS) component of NIH and the NIH Roadmap for Medical Research, the Case Comprehensive Cancer Center (P30 CA043703), the VeloSano Foundation, and a Cleveland Clinic Research Center of Excellence Award. The authors would like to thank Ken Kula from the Department of Medical Art and Photography at Cleveland Clinic for the illustrations within this manuscript. Publisher Copyright: {\textcopyright} 2022, eLife Sciences Publications Ltd. All rights reserved.",
year = "2022",
month = jan,
doi = "10.7554/eLife.63998",
language = "English",
volume = "11",
journal = "eLife",
issn = "2050-084X",
}