1767-P: Inflammatory Triggers of Lipolysis Act through IRE1 in Adipocytes

Hormones and inflammation can promote adipocyte lipolysis. Inflammation-induced insulin resistance can favor lipolysis, but the cellular mediators of unique lipolytic triggers are ill-defined. We found that ER stress discriminates inflammation-induced adipocyte lipolysis versus adrenergic-mediated lipolysis typical of hormones. Tauroursodeoxycholic acid (TUDCA) blocked adipocyte-autonomous lipolysis from multiple inflammatory ligands, including bacterial peptidoglycan (PGN), lipopolysaccharide (LPS) and tumor necrosis factor (TNF). TUDCA did not alter isoproterenol-induced lipolysis. Inhibiting inositol-requiring protein 1 (IRE1) kinase activity was sufficient to block lipolysis caused by inflammatory triggers and thapsigargin-induced ER stress. Tissue-specific deletion of IRE1 in mice confirmed that adipocyte-resident IRE1 was required for inflammatory ligand-induced lipolysis in adipose tissue. IRE1 kinase activity was dispensable for isoproterenol-induced lipolysis in adipocytes and adipose tissue. We found no role for typical unfolded protein responses as a mechanism linking ER stress to lipolysis, since IRE1 Rnase activity was not associated with changes in adipocyte lipolysis and adipose tissue from GRP78/BiP+/- mice had no change in lipolysis compared to littermate mice. Inhibiting IRE1 kinase activity blocked adipocyte NF-κB activation and Interleukin-6 (IL6) production in response to inflammatory ligands. However, inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signaling in adipocytes, which further supported the concept that inflammatory triggers of lipolysis can work independent of hormone responses, including insulin resistance. Our results are consistent with IRE1-linked ER stress mediating an inflammation-induced lipolytic program independently from hormonal regulation of lipolysis. Targeting components of IRE1-kinase signaling may have value in obesity and inflammatory lipid disorders. Disclosure K.P. Foley: None. Y. Chen: None. K. Kwok: None. N.G. Barra: None. A.K. Tamrakar: None. Y. Liu: None. J.D. Schertzer: None. Funding Canadian Institutes of Health Research