Online_appendix_30-9-20.pdf (393.58 kB)
CB1 and GLP-1 receptors cross-talk provides new therapies for obesity
figureposted on 2020-11-03, 21:48 authored by Ada AdminAda Admin, Philippe Zizzari, Rongjun He, Sarah Falk, Luigi Bellocchio, Camille Allard, Samantha Clark, Thierry Lesté-Lasserre, Giovanni Marsicano, Christoffer Clemmensen, Diego Perez-Tilve, Brian Finan, Daniela Cota, Carmelo Quarta
GLP-1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity, but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally-restricted cannabinoid-1 receptor (CB1R) inhibitors, which are devoid of the neuropsychiatric side-effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the co-administration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies, by promoting negative energy balance. This co-treatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the anti-obesity and anti-diabetic effects of currently available GLP-1R agonists.