Abstract
Obesity associates with inflammation, insulin resistance, and higher blood lipids. It is unclear if immune responses facilitate lipid breakdown and release from adipocytes via lipolysis in a separate way from hormones or adrenergic signals. We found that an ancient component of ER stress, inositol-requiring protein 1 (IRE1), discriminates inflammation-induced adipocyte lipolysis versus lipolysis from adrenergic or hormonal stimuli. Our data show that inhibiting IRE1 kinase activity was sufficient to block adipocyte-autonomous lipolysis from multiple inflammatory ligands, including bacterial components, certain cytokines, and thapsigargin-induced ER stress. IRE1-mediated lipolysis was specific for inflammatory triggers since IRE1 kinase activity was dispensable for isoproterenol and cAMP-induced lipolysis in adipocytes and mouse adipose tissue. IRE1 RNase activity was not associated with inflammation-induced adipocyte lipolysis. Inhibiting IRE1 kinase activity blocked NF-κB activation, interleukin-6 secretion, and adipocyte-autonomous lipolysis from inflammatory ligands. Inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signaling in adipocytes, suggesting that inflammation can promote IRE1-mediated lipolysis independent of adipocyte insulin resistance. We found no role for canonical unfolded protein responses or ABL kinases in linking ER stress to IRE1-mediated lipolysis. Adiponectin-Cre-mediated IRE1 knockout in mice showed that adipocyte IRE1 was required for inflammatory ligand-induced lipolysis in adipose tissue explants and that adipocyte IRE1 was required for approximately half of the increase in blood triglycerides after a bacterial endotoxin-mediated inflammatory stimulus in vivo. Together, our results show that IRE1 propagates an inflammation-specific lipolytic program independent from hormonal or adrenergic regulation. Targeting IRE1 kinase activity may benefit metabolic syndrome and inflammatory lipid disorders.
Highlights
These results indicate that some aspect of endoplasmic reticulum (ER) stress participates in bacterial cell wall stimulated adipocyte lipolysis
We examined if ER stress was required for induction of lipolysis with multiple inflammatory ligands compared with lipolysis caused by the adrenergic stimulus, isoproterenol
Previous literature had never described a role for ER stress regulating a lipolytic response that is specific for inflammatory triggers of lipolysis (Fig. 7)
Summary
We confirmed that 10 μM KirA8 blocked the RNase activity of IRE1 evinced by lower levels of spliced XBP1 in adipocytes treated with thapsigargin (Fig. 2D) These data suggest that IRE1 kinase activity (but not RNase activity) propagates inflammation-induced adipocyte lipolysis from a bacterial cell wall component. The increase in expression of BiP and CHOP induced by thapsigargin was sensitive to KirA6, whereas higher levels of spliced XBP1 (sXBP1), a key target of IRE1 RNase activity, were not affected by KirA6 These data support the concept that IRE1 kinase activity rather than RNase activity regulates lipolysis induced by inflammatory, but not hormonal, stimuli, independent of canonical UPR signaling in adipocytes. LPS-stimulated Il6 secretion was partially inhibited by KirA6 in BMDMs (Fig. 4F) These data support a role for IRE1 kinase activity in mediating Il6 secretion in response to inflammatory stimuli in adipocytes. Conditions with different letters (a, b) denote a statistical difference compared with all other conditions without the same letter
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
