ER stress dictates inflammatory, but not hormonal, lipolytic triggers in adipocytes

Objective Obesity is characterized by inflammation that can impair endocrine control of cell metabolism. The triggers and stress responses of these immune‐mediated defects are ill‐defined. There is a reciprocal relationship between inflammation and lipolysis in adipocytes, but hormones and adrenergic signals can also stimulate lipolytic programs in adipocytes. This study aimed to identify the cell stress responses that differentiate inflammatory and hormonal triggers of lipolysis in adipocytes. Methods Lipolysis was measured by glycerol release from 3T3‐L1 adipocytes treated with inhibitors of ER stress, inositol‐requiring protein 1α (IRE1α) or tyrosine kinases before stimulation with inflammatory lypolytic stimuli. The inflammatory stimuli included bacterial peptidoglycan, lipopolysaccharide, and tumor necrosis factor. The Hormonal or adrenergic stimuli tested included isoproterenol and forskolin. Inflammation was characterized by Il6 secretion and NF‐κβ activity. Results Inhibition of the kinase activity of IRE1α was sufficient to block lipolysis and Il6 secretion caused by thapsigargin‐induced ER‐stress in adipocytes. Inhibition of IRE1α kinase activity blocked augmented lipolysis from inflammatory, but not hormonal stimuli. Inhibition of IRE1α also blocked augmented Il6 secretion from all inflammatory stimuli. Inhibition of IRE1α blocked the increased NF‐κB activity from all inflammatory stimuli except for lipopolysaccharide. Inhibition of ABL kinases with imatinib did not alter lipolysis. Inhibition of IRE1α RNase activity did not alter lipolysis. The potent RIPK2 inhibitor ponatinib blocked lipolysis, Il6 secretion, and NF‐κβ activation stimulated by peptidoglycan, but did not alter lipolysis from other inflammatory stimuli, despite attenuated Il6 secretion. Conclusions The ER stress sensor IRE1α is essential for inflammation‐induced lipolysis and Il6 secretion in adipocytes. Neither RIPK2 nor NF‐κβ can fully capture the IRE1α lipolyitic pathway from inflammatory stimuli. These findings show that IRE1α discriminates inflammation‐induced lipolysis linked to ER stress from hormonal or adrenergic triggers of adipocyte lipolysis. Support or Funding Information This research is supported by operating grants to JDS from the Natural Sciences and Engineering Research Council (NSERC). JDS held CDA Scholar (SC‐5‐12‐3891‐JS) and CIHR New Investigator awards (MSH‐136665) and holds a Canada Research Chair in Metabolic Inflammation. BD was supported by an Ontario Graduate Scholarship (OGS). KF is supported by an NSERC postdoctoral fellowship. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .