Investigating the rapid activation of the futile creatine cycle via genetic manipulation
Bibliographic record
Abstract
Brown adipose tissue (BAT) generates heat from macronutrient-derived energy in a process called non-shivering thermogenesis.Futile substrate cycles that consume ATP without performing work are thermogenic systems with the potential to combat obesity and metabolic diseases.The futile creatine cycle (FCC) contributes to adipocyte thermogenesis by triggering ATP turnover through the coordinated activities of creatine kinase B (CKB) and tissue non-specific alkaline phosphatase (TNAP).We recently identified glycerol as an allosteric activator of TNAP that resultantly amplifies FCC activity.When glycerol accumulates within brown adipocytes, it is exported out by aquaglyceroporins.In this present study, we set out to ascertain whether genetic manipulation of glycerol transport serves as a mode of facultative FCC activation, hypothesizing that preventing glycerol efflux would trap glycerol intracellularly and present an opportunity to rapidly activate the FCC through enhanced TNAP activity.By mining ribosome profiling data, we validated aquaporin 7 (Aqp7) as the most abundant glycerol transporter in BAT.In immortalized brown adipocytes, knockdown of Aqp7 resulted in decreased glycerol efflux concomitant with increased intracellular glycerol following noradrenaline-stimulated lipolysis.To translate this successful 'trapping' to FCC activity, we performed a series of in vitro and ex vivo respirometry experiments.Unexpectedly, intracellular glycerol accumulation decreased noradrenaline-stimulated respiration in both immortalized and mature brown adipocytes.Moreover, adipocyte-specific knockdown of Aqp7 in vivo resulted in decreased whole-body energy expenditure.While these findings shed light on the regulatory role of glycerol in thermogenesis, it is unclear whether excess intracellular glycerol decreases respiratory capacity in brown adipocytes due to metabolic defects or BAT whitening.Therefore, further investigation is required to establish the suitability of Aqp7 in BAT as a target for FCC hyperactivation.Table 1.0 -List of
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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) | 0.000 | 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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".