Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis
Bibliographic record
Abstract
Ceramides play a central role in human health and disease, yet their role as systemic signaling molecules remain poorly understood. In this work, we identify formyl peptide receptor 2 (FPR2) as a membrane receptor that specifically binds long-chain ceramides (C14 to C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis through G i cyclic adenosine monophosphate signaling pathways, an effect that is reversed in the absence of FPR2. We present three cryo–electron microscopy structures of FPR2 in complex with G i trimers bound to C16:0, C18:0, and C20:0 ceramides. The hydrophobic tails are deeply embedded in the orthosteric ligand pocket, which has a limited amount of plasticity. Modification of the ceramide binding motif in closely related receptors, such as FPR1 or FPR3, converts them from inactive to active ceramide receptors. Our findings provide a structural basis for adipocyte thermogenesis mediated by FPR2.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".