(P13-18-26) Inhibition of peripheral Cannabinoid 1 Receptor (CB1R) Ameliorates High-Fat, High-Sugar Diet–Induced Cardiac Hypertrophy and Metabolic Dysfunction in Mice

Objectives: Obesity is associated with cardiac remodeling characterized by cardiomyocyte hypertrophy and fibrosis, which can ultimately progress to heart failure. Activation of cannabinoid 1 receptor (CB1R) has been implicated in metabolic dysfunction and cardiovascular pathology. This study aimed to determine whether inhibition of peripheral CB1R signaling attenuates high-fat, high-sugar diet (HFHSD)–induced cardiometabolic dysfunction in mice.

Methods: Six-week-old C57BL/6 mice were fed either a normal chow diet (NCD) or HFHSD for 8 weeks. After this period, HFHSD-fed mice were subdivided into three groups: HFHSD + Vehicle, HFHSD + ACEA (CB1 agonist), and HFHSD + JD-5037 (peripheral CB1 inverse agonist). Treatments were administered via intraperitoneal injection for 14 days. At study completion, heart and metabolic tissues were collected and analyzed using histological and biochemical methods.

Results: After 8 weeks, HFHSD-fed mice exhibited significant body weight gain. During the subsequent 14-day treatment period, JD-5037 significantly reduced body weight compared with HFHSD controls, whereas other groups showed minimal changes. JD-5037–treated mice displayed modestly lower heart weight compared with HFHSD controls, suggesting attenuation of diet-induced cardiac hypertrophy. Wheat germ agglutinin (WGA) staining further demonstrated reduced cardiomyocyte cross-sectional area in JD-5037-treated mice relative to HFHSD controls, whereas ACEA treatment significantly increased cardiomyocyte size. Additionally, JD-5037 improved several metabolic parameters, including reductions in fasting and fed blood glucose levels, liver weight, white adipose tissue mass, serum cholesterol, and hepatic triglyceride levels.

Conclusions: Inhibition of peripheral CB1R with JD-5037 mitigates HFHSD-induced cardiomyocyte hypertrophy and improves metabolic dysfunction, whereas CB1R activation via ACEA promotes cardiomyocyte hypertrophy. These findings highlight the role of CB1R signaling in cardiometabolic remodeling and suggest that targeting CB1R may represent a promising therapeutic strategy to mitigate obesity and associated cardiac hypertrophy.

Funding Sources: USDA (2024-67018-42461) and Oklahoma Center for the Advancement of Science & Technology (HR23-060)