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Thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice

In brown adipose tissue, thermogenesis is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase. Them1 is highly upregulated by cold ambient temperature, where it reduces fatty acid availability and limits thermogenesis. Here, we show that Them1 regulates...

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Autores principales: Li, Yue, Imai, Norihiro, Nicholls, Hayley T., Roberts, Blaine R., Goyal, Samaksh, Krisko, Tibor I., Ang, Lay-Hong, Tillman, Matthew C., Roberts, Anne M., Baqai, Mahnoor, Ortlund, Eric A., Cohen, David E., Hagen, Susan J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190112/
https://www.ncbi.nlm.nih.gov/pubmed/34108467
http://dx.doi.org/10.1038/s41467-021-23595-x
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author Li, Yue
Imai, Norihiro
Nicholls, Hayley T.
Roberts, Blaine R.
Goyal, Samaksh
Krisko, Tibor I.
Ang, Lay-Hong
Tillman, Matthew C.
Roberts, Anne M.
Baqai, Mahnoor
Ortlund, Eric A.
Cohen, David E.
Hagen, Susan J.
author_facet Li, Yue
Imai, Norihiro
Nicholls, Hayley T.
Roberts, Blaine R.
Goyal, Samaksh
Krisko, Tibor I.
Ang, Lay-Hong
Tillman, Matthew C.
Roberts, Anne M.
Baqai, Mahnoor
Ortlund, Eric A.
Cohen, David E.
Hagen, Susan J.
author_sort Li, Yue
collection PubMed
description In brown adipose tissue, thermogenesis is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase. Them1 is highly upregulated by cold ambient temperature, where it reduces fatty acid availability and limits thermogenesis. Here, we show that Them1 regulates metabolism by undergoing conformational changes in response to β-adrenergic stimulation that alter Them1 intracellular distribution. Them1 forms metabolically active puncta near lipid droplets and mitochondria. Upon stimulation, Them1 is phosphorylated at the N-terminus, inhibiting puncta formation and activity and resulting in a diffuse intracellular localization. We show by correlative light and electron microscopy that Them1 puncta are biomolecular condensates that are inhibited by phosphorylation. Thus, Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 provides fine-tuning of thermogenesis and energy expenditure.
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spelling pubmed-81901122021-07-01 Thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice Li, Yue Imai, Norihiro Nicholls, Hayley T. Roberts, Blaine R. Goyal, Samaksh Krisko, Tibor I. Ang, Lay-Hong Tillman, Matthew C. Roberts, Anne M. Baqai, Mahnoor Ortlund, Eric A. Cohen, David E. Hagen, Susan J. Nat Commun Article In brown adipose tissue, thermogenesis is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase. Them1 is highly upregulated by cold ambient temperature, where it reduces fatty acid availability and limits thermogenesis. Here, we show that Them1 regulates metabolism by undergoing conformational changes in response to β-adrenergic stimulation that alter Them1 intracellular distribution. Them1 forms metabolically active puncta near lipid droplets and mitochondria. Upon stimulation, Them1 is phosphorylated at the N-terminus, inhibiting puncta formation and activity and resulting in a diffuse intracellular localization. We show by correlative light and electron microscopy that Them1 puncta are biomolecular condensates that are inhibited by phosphorylation. Thus, Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 provides fine-tuning of thermogenesis and energy expenditure. Nature Publishing Group UK 2021-06-09 /pmc/articles/PMC8190112/ /pubmed/34108467 http://dx.doi.org/10.1038/s41467-021-23595-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Li, Yue
Imai, Norihiro
Nicholls, Hayley T.
Roberts, Blaine R.
Goyal, Samaksh
Krisko, Tibor I.
Ang, Lay-Hong
Tillman, Matthew C.
Roberts, Anne M.
Baqai, Mahnoor
Ortlund, Eric A.
Cohen, David E.
Hagen, Susan J.
Thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice
title Thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice
title_full Thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice
title_fullStr Thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice
title_full_unstemmed Thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice
title_short Thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice
title_sort thioesterase superfamily member 1 undergoes stimulus-coupled conformational reorganization to regulate metabolism in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190112/
https://www.ncbi.nlm.nih.gov/pubmed/34108467
http://dx.doi.org/10.1038/s41467-021-23595-x
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