1767-P: Inflammatory Triggers of Lipolysis Act through IRE1 in Adipocytes
Bibliographic record
Abstract
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
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.020 | 0.011 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".