Endocannabinoid system and metabolic syndrome

Abstract

The increasing prevalence of metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major challenge in the pathophysiology of cardiometabolic diseases. In this context, the identification of novel regulatory mechanisms and potential therapeutic targets has become a major focus of research. The endocannabinoid system (ECS) has emerged as a key regulator of metabolic homeostasis. Current understanding has evolved from the classical concept centered on cannabinoid receptors CB1 and CB2 to the broader concept of the endocannabinoidome, a complex network of lipid mediators, biosynthetic and degradative enzymes, and multiple receptors that regulate metabolic and inflammatory processes.

The best-characterized endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), play important roles in the regulation of energy balance, glucose and lipid metabolism, pancreatic function, inflammation, and oxidative stress. Endocannabinoid system overactivity, commonly observed in obesity and MetS, is associated with increased appetite, adipose tissue expansion, insulin resistance, dyslipidemia, and ectopic lipid accumulation in metabolically active organs such as the liver.

In addition to CB1 and CB2, several other components are part of this expanded signaling network, including the transient receptor potential vanilloid type 1 (TRPV1), the G protein-coupled receptor 55 (GPR55), and the peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ). These signaling pathways participate in the regulation of insulin sensitivity, lipogenesis, fatty acid oxidation, and inflammatory responses. TRPV1 contributes to the regulation of energy homeostasis, inflammatory signaling, and oxidative stress in metabolically active tissues, whereas CB2 is primarily associated with immunomodulatory and anti-inflammatory effects. In contrast, CB1 activation promotes hepatic lipogenesis and the progression of MASLD, while modulation of PPARα and other endocannabinoidome-related pathways may enhance fatty acid β-oxidation, reduce oxidative stress, and attenuate metabolic inflammation. GPR55 has also been proposed as a functional component of the endocannabinoidome involved in metabolic and inflammatory signaling.

Modulation of the ECS and the endocannabinoidome has emerged as a promising therapeutic strategy for cardiometabolic diseases. Cannabinoids and other compounds targeting this signaling network have shown encouraging results in preclinical models of obesity, type 2 diabetes, and MASLD. These advances provide new opportunities for the development of therapeutic approaches aimed at preventing and treating the metabolic complications associated with MetS.