Introduction: GPR43 is a receptor for short-chain fatty acids with novel therapeutic potential in treating obesity and associated metabolic diseases including Type 2 diabetes (T2D). Skeletal and cardiac muscle are both functionally impaired in these disease states, highlighting the role of GPR43 in these muscles of interest. GPR43 influences parameters of systemic health including inflammation, immunity, carcinogenesis, gastrointestinal peptide release and metabolic health. Therefore, selective manipulation of GPR43 function may be a means of countering the growing epidemic of metabolic diseases including obesity and T2D. The aim of this study is to identify the effects of GPR43 on known markers of muscle metabolism.
Methods: C2C12 skeletal muscle myotubes and H9c2 cardiomyoblasts were utilised to measure the effects of phenylacetamide (PA), an agonist for GPR43, on markers of muscle metabolism in a dose-dependent manner. Gene and protein expression of markers of metabolism were measured by real-time PCR and western blotting, respectively. Effects on metabolic activity were determined using the MTT assay.
Results: GPR43 activation with PA increased JNK and AMPKαprotein expression in C2C12 myotubes (p ≤ 0.05; n = 6-8/group). In the H9c2 cardiomyoblasts, ERK 1/2 protein was increased and PTP1b mRNA expression decreased by PA treatment (p ≤ 0.05; n = 3-9/group). These results indicate that metabolic activity was decreased by PA in skeletal muscle but increased in cardiac muscle cells (p ≤0.05; n = 9-11/group). Functional studies to determine the effect of GPR43 on mitochondrial respiration and glycolysis are currently underway.
Conclusion: This work supports dose and tissue dependent effects of activating GPR43, suggesting possible opposing effects of GPR43 in skeletal and cardiac muscle. This may have implications for the development of GPR43 as a drug target for obesity and associated metabolic diseases.
Acknowledgement: LMC was supported by the National Heart Foundation of Australia.