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

Authors

Romain Barbosa, Julia Leemput, Patricia Passilly-Degrace, Océane Pointeau, Chloé Buch, Jean-Paul Pais de Barros, Maéva Loriot, Amélie Lainé, Lukas Buet, Pablo Ortega-Deballon, Bruno Vergès, Laurent Demizieux, Tony Jourdan, Pascal Degrace

Published in

Diabetologia. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

Visceral adipose tissue (VAT) dysfunction is a major determinant of obesity-related metabolic complications. Circulating endocannabinoids (ECs) correlate positively with visceral fat mass and metabolic risk, suggesting that adipose tissue-derived ECs may contribute to adipocyte dysfunction and systemic metabolic alterations. Although adipocytes possess the enzymatic machinery for EC synthesis, the depot-specific regulation of EC production and the contribution of insulin resistance to EC overproduction in metabolic diseases remain poorly defined.
We quantified the dynamic production of the major ECs 2-arachidonoylglycerol (2-AG) and anandamide (AEA) and related N-acylethanolamines (NAEs) using ex vivo explants of VAT and subcutaneous adipose tissue (SAT) from obese mice and from individuals with obesity but without type 2 diabetes and those with both obesity and type 2 diabetes compared with their controls. Paired VAT and SAT samples from the same individuals were analysed. Mechanistic regulation of EC production was explored using pharmacological modulation, cannabinoid receptor type 1-deficient mice and cross-species transcriptomic profiling of VAT.
2-AG was the predominant species produced by human adipose tissue, with VAT exhibiting a 1.9-fold higher intrinsic production than SAT (p<0.001). Obesity alone did not significantly increase EC secretion from either depot. In contrast, VAT explants from individuals with type 2 diabetes showed an increase in EC production (1.7-fold for 2-AG [p<0.05] and 1.8-fold for AEA [p<0.05]) compared with control individuals, whereas SAT remained largely unaffected. AEA production by VAT was positively correlated with chronic glycaemic impairment (ρ=0.4786, p=0.003 for HbA_1c; ρ=0.3445, p=0.034 for fasting plasma glucose). Comparative transcriptomic analysis of mouse and human VAT revealed that type 2 diabetes, but not obesity alone, was associated with the repression of insulin-sensitive adipocyte genes, activation of inflammatory and lipid mediator pathways, and upregulation of purinergic receptor expression, consistent with an increased availability of lipid precursors.
Insulin resistance and severe adipocyte metabolic dysregulation, rather than adiposity alone, appear to be the primary determinants of depot-specific EC overproduction. Our findings identify VAT as a major source driving elevated systemic EC levels in type 2 diabetes, highlighting the therapeutic potential of specifically targeting visceral adipose EC signalling to mitigate downstream metabolic complications.

PMID:
42831899
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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