Role of Fatty Acid Amide Hydrolase (FAAH) in health and disease: focus on neurodegenerative disorders and obesity

Fatty acid amide hydrolase is a serine hydrolase, which regulates the levels of signalling lipids called endocannabinoids in body. Endocannabinoid signalling via cannabinoid receptors (CB1 and CB2) has been implicated in a number of biological and pathological conditions. As such, a number of drugs targeting endocannabinoid signalling system have been synthesised to alleviate symptoms of various diseased conditions like pain, stress, anxiety and other neurological disorders. Very recently, though, a clinical trial tragedy happened with one of the FAAH inhibitors, involving death of a healthy volunteer and hospitalisation of other four. This event put a serious question mark on the whole FAAH pharmacology. Initial findings suggested that an excessive dose of the FAAH inhibitor might have been used for the clinical trial and that the drug candidate had other off targets. In the current study, we tried to understand the effect of FAAH in more detail, so we performed brain and liver omics studies of the FAAH knockout mice. We observed a number of changes both in the lipidome and in the proteome, which we are reporting in this study. In addition, together with extensive pathway analysis focusing on clinical relevance of FAAH on human subjects, we carried out more targeted studies showing specific role of FAAH in neurodegeneration and obesity.