Inflammation promotes adipocyte lipolysis via IRE1 kinase
| Autor: | Brandyn D. Henriksbo, Kieran Kwok, Akhilesh K. Tamrakar, Wendy Chi, Yong Chen, Mark Heal, Nicole G. Barra, Kevin P. Foley, Yong Liu, Brittany M. Duggan, Jonathan D. Schertzer |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
WT wild type obesity medicine.medical_treatment immunometabolism Adipose tissue Hormone-sensitive lipase White adipose tissue Biochemistry TKI tyrosine kinase inhibitor TLR4 toll-like receptor 4 Mice PVDF polyvinylidene difluoride chemistry.chemical_compound UPR unfolded protein response 0302 clinical medicine ERK extracellular signal-regulated kinase HSL hormone sensitive lipase Adipocyte Adipocytes cytokine Insulin SVF stromal vascular fraction FK565 heptanoyl-γ-D-glutamyl-L-meso-diamino-pimelyl-D-alanine Phosphorylation ABL Abelson murine leukemia viral oncogene homolog TNF tumor necrosis factor 0303 health sciences Grp78/BiP binding immunoglobulin protein or heat shock 70 kDa protein 5 biology PGN peptidoglycan Chemistry NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells NF-kappa B WAT white adipose tissue BMDM bone-marrow-derived macrophage Il(6) interleukin XBP1 X-box binding protein 1 Adipose Tissue Cytokines LPS lipopolysaccharide ER stress SEAP secreted alkaline phosphatase Signal Transduction Research Article Proto-oncogene tyrosine-protein kinase Src AKO adipose knockout medicine.medical_specialty ATF6 activating transcription factor 6 Lipolysis IRE1 inositol-requiring enzyme 1 Protein Serine-Threonine Kinases CHOP C/EBP homologous protein adipocyte metabolic syndrome 8-Br-cAMP 8-bromoadenosine 3′ 5′-cyclic monophosphate ER endoplasmic reticulum endocrinology HEK human embryonic kidney 03 medical and health sciences Insulin resistance lipid 3T3-L1 Cells TUDCA tauroursodeoxycholic acid Internal medicine medicine Animals 4-PBA 4-phenylbutyric acid RIPK2 receptor interacting serine/threonine kinase 2 Kinase activity Molecular Biology Protein kinase B 030304 developmental biology Inflammation ATGL adipose triglyceride lipase 030102 biochemistry & molecular biology Macrophages Membrane Proteins Cell Biology medicine.disease Insulin receptor 030104 developmental biology PERK protein kinase RNA-like ER kinase Endocrinology KirA6 IRE1α kinase inhibiting RNase attenuator 6 Akt protein kinase B biology.protein Unfolded protein response PKA protein kinase A Insulin Resistance NOD nucleotide-binding oligomerization domain-containing protein 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Biological Chemistry |
| DOI: | 10.1101/2020.04.07.030148 |
| Popis: | 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 inflammation-mediated lipolysis, not adrenergic-mediated lipolysis. Bacterial and cytokine-induced lipolysis required adipocyte IRE1 kinase activity, but not IRE1 RNase activity typical of the ER stress-related 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. |
| Databáze: | OpenAIRE |
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