α/β-hydrolase domain 6 (ABHD6) is a lipase linked to physiological functions affecting energy metabolism. Brain ABHD6 degrades 2-arachidonoylglycerol and thereby modifies cannabinoid receptor signalling. However, its functional role within mesoaccumbens circuitry critical for motivated behaviour and considerably modulated by endocannabinoids was unknown. Using three viral approaches, we show that control of the nucleus accumbens by neuronal ABHD6 is a key determinant of body weight and reward-directed behaviour in male mice. Contrary to expected outcomes associated with increasing endocannabinoid tone, loss of ABHD6 in nucleus accumbens, but not ventral tegmental area, neurons completely prevents diet-induced obesity, reduces food- and drug-seeking and enhances physical activity without affecting anxiodepressive behaviour. These effects are explained by attenuated inhibitory synaptic transmission onto medium spiny neurons. ABHD6 deletion in nucleus accumbens neurons and dopamine ventral tegmental area neurons produces contrasting effects on effortful responding for food. Intraventricular infusions of an ABHD6 inhibitor also restrain appetite and promote weight loss. Together, these results reveal functional specificity of pre- and post-synaptic mesoaccumbens neuronal ABHD6 to differentially control energy balance and propose ABHD6 inhibition as a potential anti-obesity tool.

α/β-水解酶结构域 6 （ABHD6） 是一种与影响能量代谢的生理功能相关的脂肪酶。脑 ABHD6 降解 2-花生四烯酰甘油，从而改变大麻素受体信号。然而，它在伏隔间膜回路中的功能作用对动机行为至关重要，并受到内源性大麻素的很大程度调节尚不清楚。使用三种病毒方法，我们表明神经元 ABHD6 对伏隔核的控制是雄性小鼠体重和奖励导向行为的关键决定因素。与增加内源性大麻素张力、伏隔核但不是腹侧被盖区 ABHD6 丢失相关的预期结果相反，神经元完全防止饮食诱导的肥胖，减少食物和药物的寻求，并在不影响焦虑抑郁行为的情况下增强身体活动。这些作用可以通过减弱抑制性突触传递到中等棘神经元来解释。伏隔核神经元和多巴胺腹侧被盖区神经元中的 ABHD6 缺失对食物的费力反应产生相反的影响。ABHD6 抑制剂的脑室内输注也可抑制食欲并促进体重减轻。总之，这些结果揭示了突触前和突触后伏隔膜神经元 ABHD6 的功能特异性，以差异控制能量平衡，并提出 ABHD6 抑制是一种潜在的抗肥胖工具。