Diabetologia · 2026
Visceral fat endocannabinoid overproduction is associated with insulin resistance and tissue dysfunction in mice and humans.
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Barbosa Romain, Leemput Julia, Passilly-Degrace Patricia, Pointeau Océane, Buch Chloé, de Barros Jean-Paul Pais, Loriot Maéva, Lainé Amélie, Buet Lukas, Ortega-Deballon Pablo, Vergès Bruno, Demizieux Laurent, Jourdan Tony, Degrace Pascal
Аннотация
AIMS/HYPOTHESIS: 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.
METHODS: 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.
RESULTS: 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 HbA1c; 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.
CONCLUSIONS/INTERPRETATION: 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.
METHODS: 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.
RESULTS: 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 HbA1c; 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.
CONCLUSIONS/INTERPRETATION: 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.