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

• Type of Material: Article
• Authors: Yue Li, Beth Israel Deaconess Med Ctr; Norihiro Imai, Weill Cornell Medical College; Hayley T Nicholls, Weill Cornell Medical College; Blaine 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 Roberts, Emory University; Mahnoor Baqai, Beth Israel Deaconess Medical Center; Eric Ortlund, Emory University; David E Cohen, Weill Cornell Medical College; Susan J Hagen, Beth Israel Deaconess Medical Center
• Language: English
• Date: 2021-06-09
• Publisher: NATURE RESEARCH
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-021-23595-x
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 12
• Issue: 1
• Start Page: 3493
• End Page: 3493
• Grant/Funding Information: This work was supported by the National Institutes of Health (RO1 DK 103046 to D.E.C., S.J.H., and E.O.; R01 DK048873 to D.E.C.), the Harvard Digestive Diseases Center (P30 DK034854 to S.J.H.), and the National Institutes of Health shared-instrumentation grant program for the High Pressure Freezer (S10 OD019988-01 to S.J.H.); H.T.N is the recipient of a Pinnacle Research Award from the AASLD Foundation and T.I.K. is the recipient of a Weill Cornell Department of Medicine Pre-Career Award and acknowledges support from NIH T32DK007533.; N.I. is the recipient of an America Heart Association Postdoctoral Fellowship and S.G. was supported by a Research Science Institute/Center for Excellence in Education Summer Research Fellowship.
• Keywords: ADIPOSE TRIGLYCERIDE LIPASE; PHASE-SEPARATION; Science & Technology; Multidisciplinary Sciences; PHOSPHORYLATION; Science & Technology - Other Topics; MITOCHONDRIA; LIPID DROPLETS; FUNCTIONAL-CHARACTERIZATION; PROTEINS; FATTY-ACIDS; OXIDATION; TISSUE
• Research Categories: Health Sciences, Medicine and Surgery

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.