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

• Published in: Nature communications Vol. 12; no. 1; p. 3493
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/109; 14; 14/19; 14/28; 631/45/287/1183; 631/57/1464; 631/80/2023/2022; 631/80/458/1733; 82/29; 82/51; 82/58; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - metabolism; Adrenergic Agonists - pharmacology; Ambient temperature; Amino Acid Sequence; Animal tissues; Animals; Condensates; Electron microscopy; Energy demand; Energy expenditure; Energy Metabolism - drug effects; Fatty acids; Fatty Acids - metabolism; Humanities and Social Sciences; Intracellular; Intracellular Space - metabolism; Lipid Droplets - metabolism; Lipids; Localization; Metabolism; Mice; Mitochondria; Mitochondria - metabolism; multidisciplinary; N-Terminus; Oxidation; Oxidation-Reduction; Palmitoyl-CoA Hydrolase - chemistry; Palmitoyl-CoA Hydrolase - genetics; Palmitoyl-CoA Hydrolase - metabolism; Phosphorylation; Phosphorylation - drug effects; Protein Aggregates; Science; Science (multidisciplinary); Serine - metabolism; Stimulation; Thermogenesis; Thermogenesis - drug effects; Thioesterase
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23595-x

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. Cold exposure activates thermogenesis and fatty acid oxidation in brown fat, a process suppressed by Them1. Here, the authors show that cold induces Them1 phosphorylation and loss of puncta that suppress fatty acid use, leading to a diffuse localization and increased energy expenditure in mice.