Liraglutide ameliorates obese type 2 diabetes by regulating macrophage cholesterol metabolism and H3K27ac modification to promote M2 polarization and adipocyte thermogenic activation
- Design
- Animal study · Biomarker outcome
- Match to healthy normal-weight adults aged 55–75
- Not human evidenceVERY_INDIRECT: male mice with diet- and streptozotocin-induced obese diabetes, plus cultured macrophages.
- Could weight loss explain it?
- PossiblyWeight, glucose and visceral fat all fell in the mice, so the fat-tissue effects may partly reflect weight loss; the cell experiments show a direct cellular effect but are not a formal mediation analysis.
- Study tier
- Study tier 4VERY_LOW: a preclinical mouse and cell-culture mechanism study.
- Assessment
- Version 2 · Two independent AI reviews agreed · Oct 19, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
In male mice made obese and diabetic, 8 weeks of liraglutide lowered body weight, fasting blood glucose, insulin resistance and visceral fat, and shifted fat-tissue immune cells toward an anti-inflammatory type. Cell experiments pointed to a cholesterol-handling and gene-regulation pathway. These are animal and laboratory findings, not evidence of effects in people.
01Findings
What the study reported
- Drugs
- Liraglutide
- Comparator
- not reported in abstract
- Treatment duration
- 8 weeks
- Primary outcome
- metabolic phenotypes, adipose tissue macrophage polarization and cholesterol metabolism-related indicators
- Effect
- In mice, liraglutide reduced body weight, fasting blood glucose, HOMA-IR and visceral fat, and increased M2 macrophages and LXRα/ABCA1 activation; no numeric estimates in the abstract
- 95% confidence interval
- not reported in abstract
- Follow-up
- Not stated
- Adverse events
- not reported in abstract
- Limitations
- Mouse and cell-culture study of mechanisms with no sample size, dose or numeric results in the abstract; it does not test effects in people.
Who was studied
- Sex distribution
- male mice
- Obesity status
- required (high-fat-diet obese diabetic mouse model)
- Diabetes status
- required (high-fat diet plus streptozotocin diabetes model in mice)
- Cvd status
- not reported in abstract
- Ckd status
- not reported in abstract
- Baseline condition
- obesity-related type 2 diabetes model in mice, plus Raw264.7 macrophages in vitro
Study quality details
- Study design
- Preclinical (animal)
- Sample size
- not extracted
- Randomization
- not reported in abstract
- Blinding
- not stated
- Comparator
- not reported in abstract
- Follow up duration
- not stated
- Outcome type
- biomarker
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- VERY_INDIRECT
- Statistical precision
- no CI reported; significance stated without numbers
- Risk of bias
- not assessed
- Funding conflicts
- unclear
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- not stated in source
- Sponsor role
- not reported in abstract
- Author conflicts
- The authors declare no conflict of interest.
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
Obesity-related type 2 diabetes mellitus (O&T2DM) has become a major global public health issue. Chronic low-grade inflammation in adipose tissue is one of its core pathological features, among which excessive infiltration of M1-type macrophages and impaired function of M2-type macrophages are key drivers of inflammation. Liraglutide, a glucagon-like peptide-1 receptor agonist, exhibits significant glucose-lowering, weight-reducing, and anti-inflammatory effects. However, the molecular mechanisms by which liraglutide regulates cholesterol metabolism and epigenetic modifications in adipose tissue macrophages remain to be fully elucidated. A high-fat diet combined with streptozotocin was used to establish an O&T2DM model in male C57BL/6 mice. After 8 weeks of intervention, metabolic phenotypes, adipose tissue macrophage polarization, and cholesterol metabolism-related indicators were assessed. Raw264.7 macrophages were cultured in vitro and stimulated with IFN-γ + LPS to induce M1 polarization. Following liraglutide pretreatment, cell polarization phenotypes, the expression of genes involved in cholesterol metabolic pathways, and histone modification levels were examined. Using shRNA gene silencing, p300 inhibitor intervention, and Acetyl-CoA supplementation experiments in combination with ChIP-qPCR, the central role of the cholesterol metabolism-epigenetic axis in macrophage polarization was elucidated. Finally, a Transwell co-culture system was employed to verify the regulatory effects of liraglutide-reprogrammed macrophages on adipocyte lipid accumulation and energy metabolism. Liraglutide significantly reduced body weight, fasting blood glucose, and HOMA-IR in O&T2DM mice, decreased visceral fat accumulation, and promoted adipose tissue browning. It also increased the proportion of M2 macrophages within adipose tissue and significantly activated the key cholesterol efflux pathway LXRα/ABCA1. In vitro experiments confirmed that liraglutide pretreatment suppressed IFN-γ + LPS-induced M1 polarization and promoted the expression of M2-type markers, upregulated the expression of ABCA1, ABCG1, PPARγ, and LXRα, and increased levels of histone H3K27ac. Mechanistic studies revealed that silencing ABCA1 or LXRα reversed the liraglutide-induced increase in H3K27ac and M2 polarization. Acetyl-CoA supplementation partially restored the macrophage polarization phenotype following ABCA1 silencing. ChIP-qPCR results showed that liraglutide significantly enhanced the enrichment of H3K27ac in the promoter regions of M2 polarization genes and cholesterol metabolism genes. Co-culture experiments demonstrated that liraglutide-reprogrammed macrophages significantly promoted adipocyte thermogenic gene expression, increased mitochondrial membrane potential-dependent staining intensity, and enhanced ATPase activity via paracrine signaling, an effect that was blocked by silencing ABCA1 or LXRα. This study demonstrates that liraglutide activates the ABCA1/LXRα-mediated cholesterol metabolism pathway, upregulates histone H3K27ac modification, and drives macrophage M2 polarization, which in turn induces adipocyte lipid accumulation and mitochondrial metabolic activation via paracrine signaling. These findings provide a new molecular mechanism for the anti-inflammatory and metabolic-improving effects of liraglutide, and also offers a potential epigenetic target for the treatment of O&T2DM.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Oct 18, 2026 | 42870021 first ingestion |