Treatment of Diet-Induced Obese Rats with CB₂ Agonist AM1241 or CB₂ Antagonist AM630 Reduces Leptin and Alters...

Diet-induced obesity (DIO) is a contributor to co-morbidities, resulting in alterations in hormones, lipids, and low-grade inflammation, with the cannabinoid type 2 receptor (CB₂) contributing to the inflammatory response. The effects of modulating CB₂ with pharmacological treatments on inflammation and adaptations to the obese state are not known. Therefore, we aimed to investigate the molecular mechanisms in adipose tissue of CB₂ agonism and CB₂ antagonism treatment in a DIO model. Male Sprague Dawley rats were placed on a high-fat diet (HFD) (21% fat) for 9 weeks, then received daily intraperitoneal injections with a vehicle, AM630 (0.3 mg/kg), or AM1241 (3 mg/kg), for a further 6 weeks. AM630 or AM1241 treatment in DIO rats did not alter their body weight, food intake, or liver weight, and it had no effect on their numerous circulating cytokines or peri-renal fat pad mass. AM1241 decreased heart weight and BAT weight; both treatments (AM630 or AM1241) decreased plasma leptin levels, while AM630 also decreased plasma ghrelin and GLP-1 levels. Both treatments decreased Adrb3 and TNF-α mRNA levels in eWAT and TNF-α levels in pWAT. AM630 treatment also decreased the mRNA levels of Cnr2, leptin, and Slc2a4 in eWAT. In BAT, both treatments decreased leptin, UCP1, and Slc2a4 mRNA levels, with AM1241 also decreasing Adrb3, IL1β, and PRDM16 mRNA levels, and AM630 increasing IL6 mRNA levels. In DIO, CB₂ agonist and CB₂ antagonist treatment reduces circulating leptin in the absence of weight loss and modulates the mRNA responsible for thermogenesis.