Visceral fat endocannabinoid overproduction is associated with insulin resistance and tissue dysfunction in mice and humans.

Barbosa R.; Leemput J.; Passilly-Degrace P.; Pointeau O.; Buch C.; de Barros J.; Loriot M.; Lainé A.; Buet L.; Ortega-Deballon P. et al. · Diabetologia · 2026

**Background & Methods** This review examined endocannabinoid (EC) production in visceral adipose tissue (VAT) versus subcutaneous adipose tissue (SAT) using ex vivo explants from obese mice and humans with and without type 2 diabetes. The study employed pharmacological modulation, cannabinoid receptor 1-deficient mice, and cross-species transcriptomic profiling to explore mechanistic regulation of EC synthesis. **Key Findings** - VAT demonstrated 1.9-fold higher intrinsic production of 2-arachidonoylglycerol (2-AG) compared to SAT (p<0.001), with 2-AG identified as the predominant endocannabinoid species produced by human adipose tissue. Obesity alone did not significantly increase EC secretion from either depot. - Type 2 diabetes, but not obesity alone, was associated with elevated EC production in VAT specifically: 1.7-fold increase for 2-AG and 1.8-fold for anandamide (AEA) compared to controls (p<0.05 for both). VAT-derived AEA production positively correlated with chronic glycaemic impairment (HbA1c: ρ=0.4786, p=0.003; fasting glucose: ρ=0.3445, p=0.034). - Transcriptomic analysis revealed that type 2 diabetes was associated with repression of insulin-sensitive adipocyte genes, activation of inflammatory pathways, upregulation of purinergic receptors, and increased lipid mediator availability. Insulin resistance and adipocyte metabolic dysregulation, rather than adiposity alone, emerged as primary determinants of depot-specific EC overproduction. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** As a review article synthesizing both animal and human data, this study provides moderate-to-high evidence quality through integration of multiple methodological approaches including in vitro explant studies, genetic manipulation, and paired human tissue analysis. However, limitations include the ex vivo nature of adipose tissue experiments, which may not fully replicate in vivo physiological conditions. The human cohort size for transcriptomic analysis was not explicitly specified. The cross-sectional design of human sampling limits causal inference regarding the relationship between insulin resistance and EC overproduction. Despite these constraints, the depot-specific findings and consistent correlation between glycaemic markers and VAT-derived EC production strengthen the proposed mechanistic link between type 2 diabetes and endocannabinoid system dysfunction.

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