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

Yue Li, Norihiro Imai, Hayley T. Nicholls, Blaine R. Roberts, Samaksh Goyal, Tibor I. Krisko, Lay-Hong Ang, Matthew C. Tillman, Anne M. Roberts, Mahnoor Baqai, Eric A. Ortlund, David E. Cohen () and Susan J. Hagen ()
Additional contact information
Yue Li: Beth Israel Deaconess Medical Center
Norihiro Imai: Weill Cornell Medical College
Hayley T. Nicholls: Weill Cornell Medical College
Blaine R. Roberts: Emory University
Samaksh Goyal: Beth Israel Deaconess Medical Center
Tibor I. Krisko: Weill Cornell Medical College
Lay-Hong Ang: Beth Israel Deaconess Medical Center
Matthew C. Tillman: Emory University
Anne M. Roberts: Emory University
Mahnoor Baqai: Beth Israel Deaconess Medical Center
Eric A. Ortlund: Emory University
David E. Cohen: Weill Cornell Medical College
Susan J. Hagen: Beth Israel Deaconess Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23595-x

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