Gastric Bypass Surgery Recruits a Gut – Striatal Dopamine Pathway to Reduce Fat Appetite in Obese Rats

Roux-en-Y gastric bypass (RYGB) surgery produces well-documented improvements in maladaptive feeding behaviors, yet the underlying mechanisms remain ill-defined. As recognized mediators of fat intake, we evaluated the functional requirement of gut lipid-sensing and striatal dopamine signaling on healthier fat appetite after RYGB. We found that surgical rerouting of intestinal fat passage mobilized jejunal/ileal production of the dietary fat-derived molecule oleoylethanolamide (OEA). Vagal afferents link intestinal OEA signaling to nigrostriatal function. RYGB-treatment increased in vivo dorsal striatal dopamine release and dopamine-1-receptor density under conditions of high-fat meal consumption independently of bodyweight. Moreover, blocking OEA, vagal and dorsal striatal dopamine signaling all reversed the beneficial effects of surgery on fat appetite. Our findings suggest that RYGB re-sensitizes gut lipid-sensing to modify brain reward circuits compromised in obesity.