ECE2020 ePoster Presentations Diabetes, Obesity, Metabolism and Nutrition (142 abstracts)
Peripheral cannabinoid–1 receptor blockade potentiates the anti–obesity and anti–diabetic effects of GLP–1 mimetics
Philippe Zizzari 1 , Rongjun He 2 , Luigi Bellocchio 1 , Camille Allard 1 , Samantha Clark 1 , Leste–lasserre Thierry 1 , Giovanni Marsicano 1 , Diego Perez–Tilve 3 , Brian Finan 2 , Daniela Cota 1 & Carmelo Quarta 1
1INSERM, U1215 NeuroCentre Magendie, University of Bordeaux, Bordeaux, France; 2Novo Nordisk Research Center, Indianapolis, Indianapolis (IN), United States; 3University of Cincinnati–College of Medicine, Cincinnati, OH, USA., Department of Pharmacology and Systems Physiology, Cincinnati (OH), United States
Obesity and type–2 diabetes (T2D) represent a global health crisis. However, only a few, and often sub–effective pharmacological tools are available to treat these disorders. Though beneficial for glycemic control, GLP–1 receptor (GLP–1R) agonists show scarce weight–lowering and insulin–sensitizing efficacy.
New molecules able to selectively block the activity of the cannabinoid receptor type–1 (CB1R) in peripheral organs have been recently developed. In preclinical animal models, these non–brain penetrant drugs lead to sizable weight–loss and a global improvement in the multi–faced complications of obesity, including insulin resistance. These peripheral agents can bypass the known neuropsychiatric side–effects observed with brain–penetrant CB1R blockers.
Of note, GLP–1 release, and possibly its activity, may be negatively influenced by CB1R signalling, which implies that pharmacological inhibition of CB1R may be used as an effective approach to amplify the therapeutic benefits achieved with GLP–1R agonism.
Using genetic murine models with loss of CB1R or GLP–1R function, we found that these two metabolic receptors drive changes in food intake and body weight control via reciprocal functional interactions. CB1R knockout mice are more sensitive to the hypophagic effects of a GLP–1R agonist while a peripheral pharmacological blocker of CB1R (JD–5037) has blunted ability to lower body weight and food intake in mice lacking GLP–1R.
Such vicious interaction can be corrected pharmacologically. In diet–induced obese mice, the co–administration of JD–5037 with different types of GLP–1R agonists, including semaglutide, leads to more potent effects against obesity, insulin resistance, systemic dyslipidemia, and non–alcoholic fatty liver disease, relative to monotherapies. These benefits result from hypophagia, heightened systemic energy dissipation, and improved hepatic insulin action.
Thus, peripheral CB1R blockade may represent an effective strategy to safely amplify the anti–obesity and anti–diabetic efficacy of currently available GLP–1R agonists. Pharmacological co–targeting of CB1R and GLP–1R may help close the still–too–large gap between the anti–obesity efficacy of the available pharmacological tools relative to the efficacy of bariatric surgery, a procedure which has its risks.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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