Inflammation promotes adipocyte lipolysis via IRE1 kinase

Abstract

Obesity associates with inflammation, insulin resistance and higher blood lipids. It is unclear if immune responses facilitate lipolysis separate from hormone or adrenergic signals. We found that an ancient component of ER stress, inositol-requiring protein 1 (IRE1), discriminates inflammation-induced adipocyte lipolysis versus lipolysis regulated by adrenergic or hormonal stimuli. 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. Adipocyte-specific deletion of IRE1 in mice prevented inflammatory ligand-induced lipolysis in adipose tissue. 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. We found no role for canonical unfolded protein responses (UPR) or ABL kinases in linking ER stress to lipolysis.Lipolysis was unchanged in adipose tissue from GRP78/BiP +/compared to littermate mice.Tyrosine kinase inhibitors (TKIs) such as imatinib, which reduce ER stress and IRE1 RNase activity, did not alter lipolysis from inflammatory stimuli. Inhibiting IRE1 kinase activity blocked adipocyte NF-κB activation and Interleukin-6 (Il6) production due to inflammatory ligands.Inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signalling in adipocytes. Therefore, inflammation can promote IRE1-mediated lipolysis independent of adipocyte insulin resistance. Our results show that IRE1 propagates an inflammation-specific lipolytic program independent from hormonal or adrenergic regulation, including insulin resistance. Targeting IRE1 kinase activity may benefit metabolic syndrome and inflammatory lipid disorders. SignificanceAdipocytes maintain metabolic homeostasis by storing nutrients and releasing lipids into the blood via lipolysis. Catecholamines stimulate adrenergic-mediated lipolysis, whereas insulin inhibits lipolysis. Obesity is associated with elevated blood lipids and inflammation, which can impair insulin-mediated suppression of lipolysis (i.e. insulin resistance). It is unclear if inflammatory triggers of lipolysis require insulin resistance or if specific lipolytic triggers engage distinct cell stress components. We found that a specific ER stress response was required for inflammationmediated lipolysis, not adrenergic-mediated lipolysis. Bacterial and cytokine-induced lipolysis required adipocyte IRE1 kinase activity, but not IRE1 RNase activity typical of the ER stressrelated unfolded protein response. We propose that inflammatory triggers of lipolysis engage IRE1 kinase independent of catecholamine and hormone responses, including insulin resistance. Graphical AbstractIRE1 kinase activity promotes an inflammation-specific adipocyte lipolytic program that is separate from hormonal or adrenergic regulation of lipolysis.

Temporal dynamics of the multi-omic response to endurance exercise training across tissues

“…NK cells are the most exercise-responsive immune cells 103 and may play a role in limiting adipocyte hypertrophy 104 . Furthermore, previous studies have identified an association between immune cell recruitment and lipolysis 105–108 . While adipose immune responses are most often associated with pathogenic inflammation induced by obesity 109,110 , our data suggest an important role of increased immune cell activity in male adipose adaptation to endurance training.…”

Ablation of uncoupling protein 3 affects interrelated factors leading to lipolysis and insulin resistance in visceral white adipose tissue

“…However, it is important to highlight that both eif2α and JNK are considered “stress proteins”, thus it is possible that signaling pathways, other than that directly involved in UPR ER , could have participated in their activation. In addition to insulin resistance, ER stress is also closely associated with inflammation 31,32 …”

“…In addition to insulin resistance, ER stress is also closely associated with inflammation. 31,32 gWAT from KO mice has increased levels of monocyte chemoattractant protein 1 (MCP-1), known to induce the recruitment of monocytes and to activate proinflammatory macrophages, which in turn release inflammatory proteins. Among these, TNF-α was significantly increased in KO mice, likely contributing to blunting insulin signaling, and in enhancing lipolysis.…”

Low-quality protein modulates inflammatory markers and the response to lipopolysaccharide insult: the case of lysine

“…This phenomenon can happen through the binding of LPS (via its lipid A moiety) to its receptor toll-like receptor 4 (TLR-4) and stimulating its downstream inflammatory pathway (37). Another potential lipolytic route is through the inositol-requiring protein 1 (IRE-1), a component of the endoplasmic reticulum stress whose activation is insulin independent (38). The lipolytic cycles, feeding the circulation with free fatty acids, further stimulate the inflammatory outcomes through TLR-4 (39), dragging the system into a vicious Interestingly, the difference in body weight and composition was not related to the total energy intake (which was similar) but to energy efficiency.…”