Intracrine FFA4 signaling controls lipolysis at lipid droplets
Bibliographic record
Abstract
Abstract G-protein-coupled receptors (GPCRs) can signal from intracellular compartments but the occurrence and relevance of this phenomenon for metabolite-sensing GPCRs is largely unknown. Here, we investigate free fatty acid receptor 4 (FFA4), a metabolite-sensing GPCR activated by medium-chain and long-chain fatty acids. Using live-cell imaging, bioluminescence resonance energy transfer, super-resolution microscopy and cell fractionation, we show that FFA4 localizes to intracellular membranes, particularly endoplasmic reticulum subdomains surrounding lipid droplets, in both immortalized adipocytes and mouse adipose tissue. Upon lipolysis, locally released fatty acids appear to rapidly activate this intracellular FFA4 pool, leading to G i /o protein signaling and preferential reduction of cyclic adenosine monophosphate levels near lipid droplets. These mechanisms are required for efficient FFA4-mediated lipolysis regulation, as shown using tethered mini-Gα i/o proteins to locally inhibit G i/o signaling. These findings reveal an unexpected ‘intracrine’ GPCR signaling modality involved in the local regulation of cell metabolism, with biological and pharmacological implications.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".