The role of Alpha Beta Hydrolase 6 in the neuronal control of body weight, exercise and anxio-depressive behaviors

Obesity caught a lot of attention in the last years because of its expansion worldwide and its association with several diseases. Despite the enormous efforts of scientists trying to understand the molecular and physiological mechanisms of obesity, there is still the need to discover an effective treatment. Several studies point to the corticolimbic system as a potential modulator in appetite, physical activity and obesity. The corticolimbic system incorporates the nucleus accumbens (NAc) a brain region involved in the regulation of food reward, mood and physical activity. The NAc is mostly composed by GABAergic medium spiny neurons (MSNs) that are important for the control of energy balance. Manipulations of NAc MSNs by endocannabinoids (eCB) affects food intake and mood however additional research is necessary to understand the impact of eCB on physical activity and its rewarding effects. 2-arachidonoyl-glycerol (2-AG) is the most abundant eCB in the brain, it is synthesized in the postsynaptic neuron to activate the cannabinoid receptor type 1 (CB1R) located presynaptically. Modulation of the 2-AG accumulation is done by two enzymes: (1) monoacyglycerol lipase (MAGL) which is located at the presynaptic neuron to degrade the bulk of 2-AG, and (2) the serine hydrolase α/β-hydrolase domain 6 (ABHD6) localized at the postsynaptic neuron acting as a gatekeeper of 2-AG. ABHD6 gene deletion has been demonstrated to be protective from diet-induced obesity in mice; however, the exact mechanism of how ABHD6 exerts this action is still to be elucidated. Earlier findings from our lab reveal that viral-mediated knockout of ABHD6 selectively in NAc neurons increases 2-AG levels, reduces gamma-Aminobutyric acid (GABA) neuronal input transmission, suppresses food intake and prevents diet-induced obesity. While CB1R interventions showed efficacy for weight loss, they were notoriously associated with emotional disturbances such as suicidal thoughts. Therefore, ABHD6 inhibition could give a novel therapeutic approach for obesity without affecting mood. The aim of the current study is to identify the impact of NAc ABHD6 gene knockout on body weight, feeding, wheel running and anxio-depressive behaviors. Conditional knockout of ABHD6 NAc neurons (ABHD6NAc KO) of adult mice was accomplished using a viral Cre-LoxP approach. ABHD6NAc KO mice were generated by bilateral NAc microinjections delivering CRE recombinase or control GFP in a neuron-specific manner. After, the ABHD6NAc KO and control mice were subjected to either high fat diet or Control CHOW feeding for 12 weeks. We measured body weight gain, food intake and metabolic changes using CLAMS metabolic cages. Consequently, we gave 5 weeks running wheel access in their cages to see voluntary wheel running performance v between the groups. Finally, we evaluated behavioural impairments with the elevated plus maze, open field and forced swim test in ABHD6NAc KO mice and controls. Our results suggest that neuronal depletion of ABHD6 in the NAc diminishes body weight gain evoked by high fat diet with no significant differences in food consumption between the groups. Furthermore, we demonstrate that ABHD6 neuronal loss of function increased energy expenditure and prevented from voluntary physical inactivity induce by high fat diet feeding. In addition, we also showed that ABHD6NAc KO mice fail to show anxio-depressive behaviors after a prolong exposure to high fat diet. Taking together, these results demonstrate that focal neuronal inhibition of the ABHD6 enzyme in the NAc plays an important role in the regulation of energy balance and mood and thus potentially can provide a new treatment strategy for obesity.

Keyphrases: Rouage, Endocannabinoid, Serine hydrolase α/β-hydrolase domain 6, 2-arachidonoyl-glycerol, Cannabinoid receptor type 1, Nucleus accumbens, Obesity, Running wheel, Anxio-depressive behaviors.