(P18-030-24) Peripheral Antagonism of Cannabinoid 1 Receptor Contributes to Preventing Obesity Sex-Dependently in Aged Mice

Objectives: Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases, particularly occurring in the elderly population, and it is closely associated with metabolic disorders including obesity and type 2 diabetes. Notably, recent evidence suggests that peripheral regulation of cannabinoid 1 receptor (CB1R), especially in the liver, can be a promising therapeutic target of NAFLD treatment, but whether hepatic CB1R could affect age- or sex-associated NAFLD development is not fully understood. This study aimed to investigate the correlation between hepatic CB1R and nutritional challenges on the development of NAFLD in diet-induced obesity (DIO) aged male and female mouse models.

Methods: Eighteen-month-old male and female C57BL/6 mice were fed a normal chow diet (NCD) or a high-fat high-sugar diet (HFHSD) ad libitum for 8 weeks. Subsequently, HFHSD-fed mice received daily intraperitoneal injections of vehicle, 3 mg/kg JD-5037 (CB1R antagonist/inverse agonist), or 10 mg/kg arachidonyl-2’-chloroethylamide (ACEA; CB1R agonist) (n = 8–10 per group) for 14 consecutive days. Body weights and food intakes were carefully monitored with fed and 6 h-fasted blood glucose level measurements every 2 days.

Results: At the beginning of injections, the body weights of both male and female HFHSD-fed mice remarkably increased compared to the NCD-fed mice as controls. Compared to the vehicle-treated mice fed with HFHSD, significant decreases in body weight by JD-5037 treatment were observed in both male and female mice. Measurements of body composition support that body weight loss by JD-5037 was apparently due to the significantly reduced white adipose tissue, but there was no difference in liver weights among all treatment groups for both genders. Despite no difference in fed blood glucose levels between vehicle- and JD-5037-treated groups, JD-5037 significantly lowered blood glucose levels of DIO female mice after a 6 h-fasting condition. However, JD-5037 treatment did not make significant difference in fed and 6 h-fasted blood glucose levels of DIO male mice.

Conclusions: This study highlights the potential role of peripheral CB1R blockade in preventing obesity in the elderly by regulating body fat mass and blood glucose level sex-dependently.

Funding Sources: This study was supported by the Oklahoma Center for Advancement of Science & Technology (OCAST).