Abstract
O-1602 and O-1918 are atypical cannabinoid ligands for GPR55 and GPR18, which may be novel pharmaceuticals for the treatment of obesity by targeting energy homeostasis regulation in skeletal muscle. This study aimed to determine the effect of O-1602 or O-1918 on markers of oxidative capacity and fatty acid metabolism in the skeletal muscle. Diet-induced obese (DIO) male Sprague Dawley rats were administered a daily intraperitoneal injection of O-1602, O-1918 or vehicle for 6 weeks. C2C12 myotubes were treated with O-1602 or O-1918 and human primary myotubes were treated with O-1918. GPR18 mRNA was expressed in the skeletal muscle of DIO rats and was up-regulated in red gastrocnemius when compared with white gastrocnemius. O-1602 had no effect on mRNA expression on selected markers for oxidative capacity, fatty acid metabolism or adiponectin signalling in gastrocnemius from DIO rats or in C2C12 myotubes, while APPL2 mRNA was up-regulated in white gastrocnemius in DIO rats treated with O-1918. In C2C12 myotubes treated with O-1918, PGC1α, NFATc1 and PDK4 mRNA were up-regulated. There were no effects of O-1918 on mRNA expression in human primary myotubes derived from obese and obese T2DM individuals. In conclusion, O-1602 does not alter mRNA expression of key pathways important for skeletal muscle energy homeostasis in obesity. In contrast, O-1918 appears to alter markers of oxidative capacity and fatty acid metabolism in C2C12 myotubes only. GPR18 is expressed in DIO rat skeletal muscle and future work could focus on selectively modulating GPR18 in a tissue-specific manner, which may be beneficial for obesity-targeted therapies.
Highlights
Obesity rates and associated co-morbidities such as type two diabetes mellitus (T2DM) are increasing world-wide [1]
This study aimed to determine whether the atypical cannabinoids O-1602 and O-1918 had an effect on skeletal muscle homeostasis in both C2C12 myotubes and human primary myotubes derived from obese or obese T2DM individuals (O-1918 only), as well as gastrocnemius skeletal muscle obtained from Diet-induced obese (DIO) rats
In addition to the findings that O-1602 had on skeletal muscle in DIO, we showed that O-1602 did not cause any alteration to markers of oxidative capacity (NFATc1 and PGC1α), or the positive regulator of adiponectin signalling APPL1 in C2C12 myotubes
Summary
Obesity rates and associated co-morbidities such as type two diabetes mellitus (T2DM) are increasing world-wide [1]. Targeting these conditions may be beneficial in combination with a healthy diet and increased physical activity to help reduce the health-related costs and burdens for an individual, community and government. There is an increased triglyceride content within skeletal muscle [4], which is associated with insulin resistance [5]. Modulating the skeletal muscle to alter signalling pathways and improve metabolic homeostasis in obesity and associated co-morbidities such as T2DM may be beneficial. Cannabinoid receptors (CB) CB1 and CB2 are expressed in the skeletal muscle [8], with CB1 influencing oxidative pathways [9]. Limited research has focused on atypical cannabinoid compounds and receptors within the skeletal muscle in obesity
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