The Role of Atypical Cannabinoid Ligands O-1602 and O-1918 on Skeletal Muscle Homeostasis with a Focus on Obesity.

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.

Direct activation of the proposed anti-diabetic receptor, GPR119 in cardiomyoblasts decreases markers of muscle metabolic activity.

GPR119 agonists are emerging rapidly as a pharmaceutical treatment of diabetes. Diabetes is a known risk factor for cardiovascular disease yet the cardiac-specific consequences of GPR119 activation are unknown. This study demonstrated that GPR119 agonism in cardiac myoblasts reduces metabolic activity in high and low concentrations of fatty acids, with high concentrations of palmitate largely attenuating the effects of the GPR119 agonist, PSN632408. The effects of GPR119 activation on gene and protein markers of metabolism were dependent on fatty acid exposure. Activating GPR119 did not affect cell hypertrophy of lipid accumulation regardless of lipid exposure. These results suggest that the pathways activated in response to GPR119 modulation in cardiac muscle cells differ between healthy and metabolically dysregulated states. However regardless of the pathway activated by GPR119, these effects may cause detrimental reductions to oxidative/metabolic capacity under both conditions. Thus further development of GPR119 agonists for treating metabolic diseases is warranted.

GPR120 agonism as a countermeasure against metabolic diseases.

Obesity, type 2 diabetes mellitus and cardiovascular disease are at epidemic proportions in developed nations globally, representing major causes of ill-health and premature death. The search for drug targets to counter the growing prevalence of metabolic diseases has uncovered G-protein-coupled receptor 120 (GPR120). GPR120 agonism has been shown to improve inflammation and metabolic health on a systemic level via regulation of adiposity, gastrointestinal peptide secretion, taste preference and glucose homeostasis. Therefore, GPR120 agonists present as a novel therapeutic option that could be exploited for the treatment of impaired metabolic health. This review summarizes the current knowledge of GPR120 functionality and the potential applications of GPR120-specific agonists for the treatment of disease states such as obesity, type 2 diabetes mellitus and cardiovascular disease.

The therapeutic potential of GPR43: a novel role in modulating metabolic health.

GPR43 is a receptor for short-chain fatty acids. Preliminary data suggest a putative role for GPR43 in regulating systemic health via processes including inflammation, carcinogenesis, gastrointestinal function, and adipogenesis. GPR43 is involved in secretion of gastrointestinal peptides, which regulate appetite and gastrointestinal motility. This suggests GPR43 may have a role in weight control. Moreover, GPR43 regulates plasma lipid profile and inflammatory processes, which further indicates that GPR43 could have the ability to modulate the etiology and pathogenesis of metabolic diseases such as obesity, type 2 diabetes mellitus, and cardiovascular disease. This review summarizes the current evidence regarding the ability of GPR43 to mediate both systemic and tissue specific functions and how GPR43 may be modulated in the treatment of metabolic disease.

Is GPR119 agonism an appropriate treatment modality for the safe amelioration of metabolic diseases?

INTRODUCTION: GPR119 is a recently deorphanised G-protein coupled receptor which has been suggested to be important in mediating systemic metabolic homeostasis. Research to date has primarily focused on the ability of GPR119 to promote euglycaemia and thus as a therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Indeed, previous studies have shown that GPR119 promotes glucose-stimulated insulin secretion, pancreatic ß-cell function and glucagon-like peptide-1 release, all of which provide valid mechanisms through which GPR119 may improve systemic glucose homeostasis. AREAS COVERED: In the current review, the authors provide a brief overview of the known functions of GPR119 and then discuss the novel potential for GPR119 to regulate metabolic function in skeletal and cardiac muscle and how this may translate to improvements or impairments in systemic health. EXPERT OPINION: GPR119 is largely purported as being anti-diabetic and has been rapidly progressed to clinical trials, mainly as anti-diabetic agents. However, emerging data suggest that this class of agonists may have a detrimental effect at the level of the muscle. This may potentiate the development and progression of metabolic diseases such as T2DM. Therefore, further research is required before GPR119 receptor agonists can be prescribed with confidence as an anti-diabetic agent.

Diet-induced obesity up-regulates the abundance of GPR43 and GPR120 in a tissue specific manner.

BACKGROUND/AIMS: GPR43 and GPR120 have recently been deorphanised as receptors for fatty acids. Fatty acids mediate a variety of metabolic processes in the body, however, the effect these receptors have on metabolism is not fully understood. Here, we characterise the effect of diet-induced obesity on the expression of GPR43 and GPR120 in tissues important in maintaining metabolic health. METHODS: Six-week old male Sprague Dawley rats were fed either a high fat diet (HFD; 22% fat) or control diet (5% fat; n = 8-9/group) for 12 weeks. Rats were euthanized and the heart, liver, soleus and extensor digitorum longus (EDL) skeletal muscles were excised. GPR43 and GPR120 receptor abundance was quantified by 'real-time' PCR. RESULTS: GPR43 mRNA abundance was significantly up-regulated by a HFD in liver and soleus and EDL skeletal muscles compared to control (p ≤ 0.05). Whilst a HFD significantly up-regulated GPR120 gene transcripts in cardiac tissue and EDL skeletal muscle when compare to control (p ≤ 0.05). CONCLUSION: We have shown for the first time that up-regulation of GPR43 and GPR120 in response to a HFD, is tissue specific. This suggests these receptors have different roles in mediating metabolic function in a number of tissues in the human body.