Fatty acid amide hydrolase (FAAH) and the endocannabinoid system in obesity: Mechanistic insights and pharmacological opportunities beyond incretin-based therapies

The global obesity pandemic demands therapeutic innovation beyond incretin-based pharmacotherapy. While glucagon-like peptide-1 (GLP-1) receptor agonists have transformed obesity management, persistent challenges remain: gastrointestinal intolerance, weight-loss plateaus and post-treatment regain underscore the need for complementary and mechanistically orthogonal approaches. Fatty acid amide hydrolase (FAAH) represents a promising, though still exploratory, enzymatic target at the crossroads of appetite, reward and metabolism. This serine hydrolase regulates the degradation of both pro-orexigenic endocannabinoids, notably anandamide (AEA) and antiorexigenic N-acylethanolamines (NAEs), particularly oleoylethanolamide (OEA). Unlike direct cannabinoid type 1 receptor (CB1 receptor) antagonists, which failed clinically due to severe psychiatric toxicity, FAAH modulation may allow a more spatially and temporally constrained regulation of endogenous lipid signalling. Importantly, FAAH inhibition does not intrinsically discriminate between orexigenic and anorexigenic substrates; thus, its metabolic impact depends on tissue selectivity, substrate bias and nutritional context. By prolonging OEA signalling, FAAH inhibition has the potential to enhance peroxisome proliferator-activated receptor alpha (PPARα) and G proteincoupled receptor 119 (GPR119) pathways, promoting fatty acid β-oxidation, improving hepatic lipid handling, and amplifying nutrient-dependent GLP-1 secretion in preclinical models. However, translational evidence in humans remains limited, and the longterm metabolic efficacy of FAAH inhibition in obesity has yet to be demonstrated. This review examines FAAH biochemistry, its dysregulation in obesity, and the evolving pharmacological landscape of FAAH modulators, with particular attention to peripherally restricted and substrate-biased strategies. Rather than proposing FAAH inhibition as a standalone anti-obesity therapy, we discuss its potential role as a complementary component within multimodal treatment regimens alongside incretin-based drugs.