CB1 receptor and obesity: from the rimonabant controversy to new therapeutic perspectives

Obesity is a chronic and multifactorial disease associated with metabolic alterations, hormonal resistance, and systemic inflammation.The endocannabinoid system regulates functions in both the central nervous system and peripheral tissues, including appetite, energy metabolism, hepatic lipogenesis, insulin and leptin sensitivity, as well as the gut-brain axis.Its dysfunction is linked to visceral obesity, insulin resistance, and neuroimmune imbalance.Among its targets, the cannabinoid receptor type 1 (CB1) stands out as a therapeutic candidate.Rimonabant, a CB1 antagonist, reduced body weight and improved cardiometabolic parameters, but was withdrawn due to neuropsychiatric side effects.This prompted the development of peripheral CB1 antagonists with limited blood-brain barrier penetration and improved safety profiles.In parallel, pharmacogenomic studies have identified variants in CNR1 and SLC6A4 that influence efficacy and adverse effects, paving the way for personalized medicine.This article reviews the role of CB1, the clinical trajectory of rimonabant, and advances in peripheral antagonists.