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

Yue Li,Blaine R Roberts,Mahnoor Baqai,Samaksh Goyal,Lay-Hong Ang,David E Cohen,Anne M Roberts,Matthew C Tillman,Susan J Hagen,Eric A Ortlund,Tibor I Krisko,Norihiro Imai,Hayley T Nicholls

doi:10.1038/s41467-021-23595-x

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.

Highlights

In brown adipose tissue, thermogenesis is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-coenzyme A (CoA) thioesterase
We demonstrate that β-adrenergic stimulation with NE, which is used to mimic cold exposure, activates a signaling cascade that results in Them[1] phosphorylation and a diffuse localization
To examine whether Them[1] is S-phosphorylated after stimulation, we determined the aggregate abundance of phosphopeptides in the N-terminus of Them[1] by mass spectrometry after stimulation with phorbol 12-myristate 13-acetate (PMA; Fig. 1a, b) normalized to hormone-sensitive lipase as a housekeeping phosphopeptide that does not change with PMA stimulation (Supplementary Fig. 3)

Summary

Introduction

Thermogenesis is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase. Intracellular triglycerides are stored within lipid droplets (LD) that are juxtaposed to mitochondria in the cytoplasm[1] This close relationship facilitates the rapid transfer of fatty acids to mitochondria, which are generated by lipolysis in response to cellular energy demands[2]. A functional analysis revealed that Them[1] in punctate form suppresses fatty acid oxidation, whereas this suppression is abrogated when it is diffusely distributed in the cell cytoplasm Overall, these findings highlight the importance of Them[1] phosphorylation in the regulation of thermogenesis in BAT and lend support for targeting Them[1] for the management of obesityrelated disorders

Methods

Results

Conclusion