Inflammation promotes adipocyte lipolysis via IRE1 kinase

• Published in: The Journal of biological chemistry Vol. 296; p. 100440
• Main Authors: Foley, Kevin P., Chen, Yong, Barra, Nicole G., Heal, Mark, Kwok, Kieran, Tamrakar, Akhilesh K., Chi, Wendy, Duggan, Brittany M., Henriksbo, Brandyn D., Liu, Yong, Schertzer, Jonathan D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021; American Society for Biochemistry and Molecular Biology
• Subjects: adipocyte; cytokine; endocrinology; ER stress; immunometabolism; inflammation; lipid; lipolysis; metabolic syndrome; obesity; SVF; Il; 4-PBA; ATGL; TUDCA; ABL; BMDM; PERK; WAT; lipid; TNF; LPS; 8-Br-cAMP; NF-κB; inflammation; immunometabolism; UPR; IRE1; CHOP; KirA6; WT; obesity; cytokine; Grp78/BiP; HSL; NOD; XBP1; AKO; RIPK2; PKA; SEAP; ER stress; Akt; ER; PVDF; HEK; metabolic syndrome; FK565; TKI; PGN; adipocyte; lipolysis; ATF6; TLR4; endocrinology; ERK
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2021.100440

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.