ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity

α/β-hydrolase domain 6 (ABHD6) is a lipase linked to physiological functions affecting metabolism and body weight. Brain ABHD6 degrades 2-arachidonoylglycerol and thereby modulates cannabinoid receptor signaling. However, it’s functional role within mesoaccumbens circuitry that is critical for motivated behavior and known to be significantly modulated by endocannabinoids remained 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-relevant behavior. Contrary to expected outcomes associated with increasing endocannabinoid tone, ABHD6 loss of function in the nucleus accumbens, but not the ventral tegmental area, inhibited food reward and completely prevented diet-induced obesity and associated physical inactivity without affecting anxiodepressive behavior. 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 produced contrasting effects on food-directed behavior. Together, these results reveal functional specificity of pre- and post-synaptic mesoaccumbens neuronal ABHD6 to differentially control energy metabolism and propose ABHD6 inhibition as a potential anti-obesity tool.