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.