Beyond energy balance: 2-arachidonoylglycerol at the crossroads of obesity, inflammation, and metabolic dysfunction.

Obesity is the rising public health concern of every household to globally which can now be characterized as a pandemic. The growing prevalence of obesity draws researcher's attention for a deeper understanding of its pathologies and available therapeutic strategies. The known pathologies of the obesity only turns around chronic energy imbalance between consumed calories and calories burnt. There is need to understand intricate relationship between Gut Brain Adipose axis and the complex pathophysiology of obesity which remains incompletely understood. Thus, before a cure, we need to understand the pathology of obesity in a deeper way. Emerging evidences suggest the endocannabinoid system (ECS) as an underappreciated mediator of obesity pathogenesis. In particular, the endocannabinoid 2-arachidonoylglycerol (2-AG) levels are elevated in obesity, acting as a key signaling hub. 2-AG integrates central and peripheral pathways that govern appetite, reward-driven feeding, energy balance, adipogenesis, insulin signaling, mitochondrial function, and immune activation. This review is focussed on 2-AG as a mechanistic intersection at neuroendocrine control of energy balance with metabolic, mitochondrial, oxidative, and inflammatory processes, while critically distinguishing direct evidence for 2-AG, therapeutic gaps, and future perspectives of targeting cannabinoid pharmacology. Importantly, this review discusses that how 2-AG signaling may intersects with insulin/PI3K/AKT, AMPK, PPARs, and NF-κB pathways, amplifying metabolic dysfunction and obesity. This review provides insights on how 2-AG may target different obesity pathogenesis and may pave the way for development of newer targeted interventions. We highlight 2-AG's multi-organ signaling crosstalk and discuss how modulating the 2-AG/ECS axis may yield novel therapeutic strategies for obesity.