Online_appendix_30-9-20.pdf (393.58 kB)
CB1 and GLP-1 receptors cross-talk provides new therapies for obesity
figure
posted 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 QuartaGLP-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.