Grant: Project Grant

Overeating plays a significant role in weight gain and development of obesity. Endocannabinoids exert a major influence on the activity of brain circuits that controls motivation for palatable food. 2-Arachidonoylglycerol (2-AG) is an endocannabinoid that activates the CB1 receptor. Although increased brain endocannabinoids and signalling at CB1 receptors is widely associated with stimulation of food intake, enhanced CB1 receptor signalling at specific inhibitory neuronal populations can reduce feeding. The recently characterized serine hydrolase alpha-beta-hydrolase domain 6 (ABHD6) degrades 2-AG at the site of synthesis, ultimately increasing 2-AG levels and action at CB1R. Complete ABHD6 loss of function or inhibition in peripheral metabolic organs protects against obesity and diabetes in mice. Following our observations that an ABHD6 inhibitor restricted to the brain can prevent diet-induced obesity, we propose to use a combination of targeted genetic and central pharmacological interventions in mice to identify the neural and behavioural effects of ABHD6 loss of function on appetite control, food craving and prevention and treatment of obesity and obesity-induced mood impairments. While therapeutic interventions for appetite suppression are notoriously associated with negative side effects on mood, an ABHD6 inhibitor may offer a promising dual strategy for treating both metabolic and emotional impairments.