Is Hepatic Cannabinoid 1 Receptor a Key Driver of Obesity? Implications of the Weight-Reducing Efficacy of the Hepatotropic Inverse Agonist TM38837.

Abstract

Although an attractive approach for treating obesity-related pathologies, the development of peripherally restricted cannabinoid 1 receptor inhibitors has thus far failed to deliver drugs with clinically validated efficacy and safety margins over central nervous system (CNS)-related side effects. Challenges and frequently occurring misleading assumptions with this strategy are discussed. However, the recently reported peripherally restricted hepatotropic cannabinoid 1 receptor inverse agonist TM38837 is noteworthy due to the substantial weight loss efficacy in DIO rodents coupled with minimal CNS exposure, which suggests that such a chemotype may have clinical utility. Furthermore, hepatic cannabinoid 1 receptor upregulation is implicated as a major driver of the obese phenotype in rodents, which opposes current theories based upon experiments with genetically modified mice. Accordingly, a novel hypothesis is proposed, which implicates cannabinoid 1 receptor upregulation as a mediator of cell cycle progression, which drives lipid synthesis during the mitosis phase. The upregulation is initiated by increasing redox state and amplified by a feed-forward effect whereby cannabinoid 1 receptor activation induces cannabinoid 1 receptor upregulation by increasing expression of pro-oxidant enzymes. This mechanism is activated prematurely in the cell cycle by lifestyle factors, which are known to cause oxidative stress in hepatocytes and are associated with the development of obesity. The consequence of such aberrant cannabinoid 1 receptor upregulation is sustained lipogenesis, leading to reduced cellular ATP levels, which drive increased food intake and contribute to other pathologies.