Modes of action of obesity therapeutics: investigation and modulation of the cannabinoid 1, opioid and GLP-1 receptors as targets for treating metabolic disease

Weight-loss pharmaceuticals have traditionally targeted individual receptors or receptor systems and have struggled to reach efficacies of 5% to 10% weight loss. Newer drugs are utilising a combination approach which seeks to exploit multiple receptor systems with the advantage of lower doses and improved management of side effects. In this thesis two separate ways of recruiting multiple receptor systems to augment weight loss with drug treatment are investigated. Firstly, we used the CB1 receptor antagonist, rimonabant, and aimed to improve the efficacy and reduce the deleterious mood side effects of this drug by co-treatment with opioid receptor antagonists. Using both genetic and pharmacological approaches to eliminate specific opioid signalling in mice, we show that the ability of rimonabant to reduce body weight is enhanced by removal of mu opioid receptor (MOR) signalling, while not being greatly affected by loss kappa opioid receptor (KOR) signalling. Additionally, lack of opioid signalling, especially KOR, attenuates the mood-related effects of rimonabant in the forced swim test, a preclinical test of anti-depressants. When this drug combination was tested chronically in obese mice these positive metabolic and mood outcomes were maintained. Furthermore, we identified changes in neuronal activation in a number of nuclei known to be important in processing mood and the rewarding aspects of feeding. Together these studies offer proof of principle that using adjunct therapies can improve both the efficacy of rimonabant and its side effects. The second strategy we used for recruitment of multiple signalling pathways to enhance the therapeutic outcome of a drug was using a single compound which acts at more than one receptor. The peptide hormone oxyntomodulin (OXM) activates both the glucagon-like peptide1 receptor (GLP-1R) and the glucagon receptor (GCGR), both of which have known metabolic actions. We aimed to delineate the respective roles of the GLP-1R and the GCGR in the metabolic effects of OXM with a view that a better understanding of the physiological endpoints of OXM treatment would lead to better targets for obesity therapeutics. Chronic intracerebroventricular (ICV) administration of the peptides GLP-1, OXM or GCG resulted in a significant loss of body weight and fat. Acute ICV administration of GLP-1, OXM and GCG all significantly increased both activity of the sympathetic nerves innervating the brown adipose tissue (BAT) and BAT temperature. In the case of OXM this thermogenic effect was found to be mediated by the GLP-1 receptor. These data demonstrate a role for central GLP-1R and GCGR signalling in controlling BAT thermogenesis. Our results suggest that the increase in non-shivering thermogenesis may contribute to the anti-obesity benefits of therapies based on GLP-1R and GCGR agonism. The work contained in this thesis extends our understanding of the physiological mechanisms behind the weight loss properties of several anti-obesity drugs. The possibility of reinstating the CB1 receptor as a drug target is exciting, considering for many people it was an effective drug. Similarly, GLP1-R agonists are widely prescribed for type 2 diabetes, so a better understanding of the physiological consequences of this treatment is exceptionally important.