46 Inhibition of Lipolysis with Acipimox Targets Post-burn White Adipose Browning by Altering Macrophage Polarity
Bibliographic record
Abstract
Abstract Introduction Severe burns are accompanied by a detrimental hypermetabolic stress response that can persist for years post-injury. Our previous work revealed that, under prolonged stress, white adipose tissue (WAT) adopts brown adipose-like traits in a process termed ‘browning’. This switch, characterized by the presence of uncoupling protein 1 (UCP1), is driven by the polarization of macrophages towards an M2 phenotype. Recently, we demonstrated that inhibiting lipolysis with the clinically approved drug, Acipimox, represses the burn-induced thermogenic activation of WAT. These findings raise the possibility that elevated rates of lipolysis may play a role in regulating the macrophage polarization state after major burn. However, the interconnection between post-burn lipolysis and inflammation remains unclear. In the present study, we investigated the mechanism underlying Acipimox’s inhibitory effects on burn-induced browning. Using a mouse model of thermal injury, we determine the metabolic effects of reducing WAT lipolysis on burn-induced macrophage recruitment and M2-polarization. Methods Adult C57BL/6 mice received a 30% total body surface area scald burn. Mice were then given daily intraperitoneal injections of APX (50 mg/Kg). On day 7 post-burn, the inguinal adipose tissue depot (iWAT) was harvested for histological analyses. Flow cytometry and F4/80 staining were used to assess adipose macrophage distribution and profile, and gene expression was analyzed via qPCR. Results APX administration significantly increased mitochondrial coupling, reflected by the decrease in UCP-1 (p< 0.05) and PGC-1a (p< 0.01) levels relative to the iWAT of untreated burn mice. F4/80 immunostaining of iWAT demonstrated decreased macrophage recruitment in Acipimox treated mice (p< 0.05). Flow cytometric analysis indicated decreased macrophage infiltration at 7 days in Acipimox treated mice (p< 0.05). Furthermore, iWAT from Acipimox treated mice demonstrated a pro-inflammatory profile, indicated by a greater distribution of TLR4 positive macrophages (p< 0.05). Conclusions Previously, we showed that the administration of Acipimox effectively suppressed PKA-mediated lipolysis and improved mitochondrial coupling in adipose tissue post-burn. Here, we elucidate the mechanism underlying these metabolic changes. Importantly, we show Acipimox exerts its inhibitory effects on burn-induced WAT browning by directly modulating macrophage recruitment and the M2-polarization state. Applicability of Research to Practice Our study highlights the critical role of lipolysis in mediating the key post-burn metabolic phenomena browning and inflammation. The data presented herein validate the pharmacological inhibition of lipolysis as a potentially powerful therapeutic strategy to counteract the detrimental metabolic effects induced by burn.
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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) | 0.002 | 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".