Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms
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...
Ausführliche Beschreibung
Autor*in: |
Rebecca C Schugar [verfasserIn] Christy M Gliniak [verfasserIn] Lucas J Osborn [verfasserIn] William Massey [verfasserIn] Naseer Sangwan [verfasserIn] Anthony Horak [verfasserIn] Rakhee Banerjee [verfasserIn] Danny Orabi [verfasserIn] Robert N Helsley [verfasserIn] Amanda L Brown [verfasserIn] Amy Burrows [verfasserIn] Chelsea Finney [verfasserIn] Kevin K Fung [verfasserIn] Frederick M Allen [verfasserIn] Daniel Ferguson [verfasserIn] Anthony D Gromovsky [verfasserIn] Chase Neumann [verfasserIn] Kendall Cook [verfasserIn] Amy McMillan [verfasserIn] Jennifer A Buffa [verfasserIn] James T Anderson [verfasserIn] Margarete Mehrabian [verfasserIn] Maryam Goudarzi [verfasserIn] Belinda Willard [verfasserIn] Tytus D Mak [verfasserIn] Andrew R Armstrong [verfasserIn] Garth Swanson [verfasserIn] Ali Keshavarzian [verfasserIn] Jose Carlos Garcia-Garcia [verfasserIn] Zeneng Wang [verfasserIn] Aldons J Lusis [verfasserIn] Stanley L Hazen [verfasserIn] Jonathan Mark Brown [verfasserIn] |
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Format: |
E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2022 |
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In: eLife - eLife Sciences Publications Ltd, 2013, 11(2022) |
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Übergeordnetes Werk: |
volume:11 ; year:2022 |
Links: |
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DOI / URN: |
10.7554/eLife.63998 |
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Katalog-ID: |
DOAJ006676561 |
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520 | |a 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. | ||
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10.7554/eLife.63998 doi (DE-627)DOAJ006676561 (DE-599)DOAJ1bf775b855894d52aa435ffcd48a01d8 DE-627 ger DE-627 rakwb eng QH301-705.5 Rebecca C Schugar verfasserin aut Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. nutrition drug delivery genetic diseases gut microbiome Medicine R Science Q Biology (General) Christy M Gliniak verfasserin aut Lucas J Osborn verfasserin aut William Massey verfasserin aut Naseer Sangwan verfasserin aut Anthony Horak verfasserin aut Rakhee Banerjee verfasserin aut Danny Orabi verfasserin aut Robert N Helsley verfasserin aut Amanda L Brown verfasserin aut Amy Burrows verfasserin aut Chelsea Finney verfasserin aut Kevin K Fung verfasserin aut Frederick M Allen verfasserin aut Daniel Ferguson verfasserin aut Anthony D Gromovsky verfasserin aut Chase Neumann verfasserin aut Kendall Cook verfasserin aut Amy McMillan verfasserin aut Jennifer A Buffa verfasserin aut James T Anderson verfasserin aut Margarete Mehrabian verfasserin aut Maryam Goudarzi verfasserin aut Belinda Willard verfasserin aut Tytus D Mak verfasserin aut Andrew R Armstrong verfasserin aut Garth Swanson verfasserin aut Ali Keshavarzian verfasserin aut Jose Carlos Garcia-Garcia verfasserin aut Zeneng Wang verfasserin aut Aldons J Lusis verfasserin aut Stanley L Hazen verfasserin aut Jonathan Mark Brown verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.63998 kostenfrei https://doaj.org/article/1bf775b855894d52aa435ffcd48a01d8 kostenfrei https://elifesciences.org/articles/63998 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 |
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10.7554/eLife.63998 doi (DE-627)DOAJ006676561 (DE-599)DOAJ1bf775b855894d52aa435ffcd48a01d8 DE-627 ger DE-627 rakwb eng QH301-705.5 Rebecca C Schugar verfasserin aut Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. nutrition drug delivery genetic diseases gut microbiome Medicine R Science Q Biology (General) Christy M Gliniak verfasserin aut Lucas J Osborn verfasserin aut William Massey verfasserin aut Naseer Sangwan verfasserin aut Anthony Horak verfasserin aut Rakhee Banerjee verfasserin aut Danny Orabi verfasserin aut Robert N Helsley verfasserin aut Amanda L Brown verfasserin aut Amy Burrows verfasserin aut Chelsea Finney verfasserin aut Kevin K Fung verfasserin aut Frederick M Allen verfasserin aut Daniel Ferguson verfasserin aut Anthony D Gromovsky verfasserin aut Chase Neumann verfasserin aut Kendall Cook verfasserin aut Amy McMillan verfasserin aut Jennifer A Buffa verfasserin aut James T Anderson verfasserin aut Margarete Mehrabian verfasserin aut Maryam Goudarzi verfasserin aut Belinda Willard verfasserin aut Tytus D Mak verfasserin aut Andrew R Armstrong verfasserin aut Garth Swanson verfasserin aut Ali Keshavarzian verfasserin aut Jose Carlos Garcia-Garcia verfasserin aut Zeneng Wang verfasserin aut Aldons J Lusis verfasserin aut Stanley L Hazen verfasserin aut Jonathan Mark Brown verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.63998 kostenfrei https://doaj.org/article/1bf775b855894d52aa435ffcd48a01d8 kostenfrei https://elifesciences.org/articles/63998 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 |
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10.7554/eLife.63998 doi (DE-627)DOAJ006676561 (DE-599)DOAJ1bf775b855894d52aa435ffcd48a01d8 DE-627 ger DE-627 rakwb eng QH301-705.5 Rebecca C Schugar verfasserin aut Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. nutrition drug delivery genetic diseases gut microbiome Medicine R Science Q Biology (General) Christy M Gliniak verfasserin aut Lucas J Osborn verfasserin aut William Massey verfasserin aut Naseer Sangwan verfasserin aut Anthony Horak verfasserin aut Rakhee Banerjee verfasserin aut Danny Orabi verfasserin aut Robert N Helsley verfasserin aut Amanda L Brown verfasserin aut Amy Burrows verfasserin aut Chelsea Finney verfasserin aut Kevin K Fung verfasserin aut Frederick M Allen verfasserin aut Daniel Ferguson verfasserin aut Anthony D Gromovsky verfasserin aut Chase Neumann verfasserin aut Kendall Cook verfasserin aut Amy McMillan verfasserin aut Jennifer A Buffa verfasserin aut James T Anderson verfasserin aut Margarete Mehrabian verfasserin aut Maryam Goudarzi verfasserin aut Belinda Willard verfasserin aut Tytus D Mak verfasserin aut Andrew R Armstrong verfasserin aut Garth Swanson verfasserin aut Ali Keshavarzian verfasserin aut Jose Carlos Garcia-Garcia verfasserin aut Zeneng Wang verfasserin aut Aldons J Lusis verfasserin aut Stanley L Hazen verfasserin aut Jonathan Mark Brown verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.63998 kostenfrei https://doaj.org/article/1bf775b855894d52aa435ffcd48a01d8 kostenfrei https://elifesciences.org/articles/63998 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 |
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10.7554/eLife.63998 doi (DE-627)DOAJ006676561 (DE-599)DOAJ1bf775b855894d52aa435ffcd48a01d8 DE-627 ger DE-627 rakwb eng QH301-705.5 Rebecca C Schugar verfasserin aut Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. nutrition drug delivery genetic diseases gut microbiome Medicine R Science Q Biology (General) Christy M Gliniak verfasserin aut Lucas J Osborn verfasserin aut William Massey verfasserin aut Naseer Sangwan verfasserin aut Anthony Horak verfasserin aut Rakhee Banerjee verfasserin aut Danny Orabi verfasserin aut Robert N Helsley verfasserin aut Amanda L Brown verfasserin aut Amy Burrows verfasserin aut Chelsea Finney verfasserin aut Kevin K Fung verfasserin aut Frederick M Allen verfasserin aut Daniel Ferguson verfasserin aut Anthony D Gromovsky verfasserin aut Chase Neumann verfasserin aut Kendall Cook verfasserin aut Amy McMillan verfasserin aut Jennifer A Buffa verfasserin aut James T Anderson verfasserin aut Margarete Mehrabian verfasserin aut Maryam Goudarzi verfasserin aut Belinda Willard verfasserin aut Tytus D Mak verfasserin aut Andrew R Armstrong verfasserin aut Garth Swanson verfasserin aut Ali Keshavarzian verfasserin aut Jose Carlos Garcia-Garcia verfasserin aut Zeneng Wang verfasserin aut Aldons J Lusis verfasserin aut Stanley L Hazen verfasserin aut Jonathan Mark Brown verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.63998 kostenfrei https://doaj.org/article/1bf775b855894d52aa435ffcd48a01d8 kostenfrei https://elifesciences.org/articles/63998 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 |
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10.7554/eLife.63998 doi (DE-627)DOAJ006676561 (DE-599)DOAJ1bf775b855894d52aa435ffcd48a01d8 DE-627 ger DE-627 rakwb eng QH301-705.5 Rebecca C Schugar verfasserin aut Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. nutrition drug delivery genetic diseases gut microbiome Medicine R Science Q Biology (General) Christy M Gliniak verfasserin aut Lucas J Osborn verfasserin aut William Massey verfasserin aut Naseer Sangwan verfasserin aut Anthony Horak verfasserin aut Rakhee Banerjee verfasserin aut Danny Orabi verfasserin aut Robert N Helsley verfasserin aut Amanda L Brown verfasserin aut Amy Burrows verfasserin aut Chelsea Finney verfasserin aut Kevin K Fung verfasserin aut Frederick M Allen verfasserin aut Daniel Ferguson verfasserin aut Anthony D Gromovsky verfasserin aut Chase Neumann verfasserin aut Kendall Cook verfasserin aut Amy McMillan verfasserin aut Jennifer A Buffa verfasserin aut James T Anderson verfasserin aut Margarete Mehrabian verfasserin aut Maryam Goudarzi verfasserin aut Belinda Willard verfasserin aut Tytus D Mak verfasserin aut Andrew R Armstrong verfasserin aut Garth Swanson verfasserin aut Ali Keshavarzian verfasserin aut Jose Carlos Garcia-Garcia verfasserin aut Zeneng Wang verfasserin aut Aldons J Lusis verfasserin aut Stanley L Hazen verfasserin aut Jonathan Mark Brown verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.63998 kostenfrei https://doaj.org/article/1bf775b855894d52aa435ffcd48a01d8 kostenfrei https://elifesciences.org/articles/63998 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 |
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Rebecca C Schugar @@aut@@ Christy M Gliniak @@aut@@ Lucas J Osborn @@aut@@ William Massey @@aut@@ Naseer Sangwan @@aut@@ Anthony Horak @@aut@@ Rakhee Banerjee @@aut@@ Danny Orabi @@aut@@ Robert N Helsley @@aut@@ Amanda L Brown @@aut@@ Amy Burrows @@aut@@ Chelsea Finney @@aut@@ Kevin K Fung @@aut@@ Frederick M Allen @@aut@@ Daniel Ferguson @@aut@@ Anthony D Gromovsky @@aut@@ Chase Neumann @@aut@@ Kendall Cook @@aut@@ Amy McMillan @@aut@@ Jennifer A Buffa @@aut@@ James T Anderson @@aut@@ Margarete Mehrabian @@aut@@ Maryam Goudarzi @@aut@@ Belinda Willard @@aut@@ Tytus D Mak @@aut@@ Andrew R Armstrong @@aut@@ Garth Swanson @@aut@@ Ali Keshavarzian @@aut@@ Jose Carlos Garcia-Garcia @@aut@@ Zeneng Wang @@aut@@ Aldons J Lusis @@aut@@ Stanley L Hazen @@aut@@ Jonathan Mark Brown @@aut@@ |
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Gut microbe-targeted choline trimethylamine lyase inhibition improves obesity via rewiring of host circadian rhythms |
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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. |
abstractGer |
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. |
abstract_unstemmed |
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. |
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