Cannabigerol Alleviates Obesity-Induced Mitochondrial Dysfunction by Cardiolipin Fatty Acid Remodeling

Abstract

Until now, strategies to offset the harmful effects of obesity using phytocannabinoids have only begun to be unraveled. Therefore, we aimed to identify the possible therapeutic role of 2-week cannabigerol (CBG) treatment on intramuscular fatty acids (FAs) and lipid metabolism, with subsequent implications for mitochondrial cardiolipin composition in male Wistar rats in the context of a high-fat, high-sucrose diet-induced obesity. To elucidate underlying mechanisms, we assessed expression and cellular localization of fatty acid-handling proteins, intramuscular lipid profile, the total expression of proteins involved in FAs synthesis and metabolism, cardiolipin content and composition, cytochrome c oxidase activity, as well as superoxide dismutase (SOD) level and lipid peroxides formation using Western blotting, gas–liquid chromatography, and immunoenzymatic kits. Our findings demonstrate that CBG alleviates obesity-induced recruitment of fatty acid transporters to the plasma membrane, thereby limiting intracellular FAs influx and protecting myocytes against excess lipogenesis and subsequent lipid storage. Moreover, we also revealed obesity-related defective cardiolipin fatty-acyl chain remodeling, characterized by excess accumulation of docosahexaenoic acid, leading to increased unsaturated aldehyde formation. Importantly, CBG upregulated muscular cardiolipin and prevented the buildup of C22:6n-3, which was accompanied by elevated SOD levels and reduced formation of lipid peroxidation products, indicating enhanced cellular antioxidant defense. Hence, CBG-mediated effects may fulfill an urgent, so far unmet clinical need for treatments that can directly target muscular obesity-associated metabolic defects.