Role of the GPRC6A Receptor in Energy Metabolism: A Metabolic Characterisation of a GPRC6A Knockout Mouse Model
The GPRC6A receptor is a recently identified G protein-coupled receptor that is activated by dietary L-α-amino acids and hypothesised to play role in regulating energy metabolism. Despite that three independent research groups have developed, and employed, GPRC6A deficient animals to investigate the physiological function(s) of the receptor, the role of GPRC6A in energy metabolism is still elusive. Thus, the overall aim of the present PhD project was to delineate the role of the GPRC6A receptor in energy metabolism.
We examined 1) a role for GPRC6A in L-arginine-induced insulin release, 2) glucose- and energy metabolism in chow fed GPRC6A knockout (KO) and wild-type (WT) mice, 3) glucose and energy metabolism in high-fat diet (HFD) fed GPRC6A KO and WT mice, 4) a role for GPRC6A in forced and voluntary running and adaptations to exercise, and finally, 5) an array of plasma- and tissue biomarkers aiming to obtain insights into the underlying molecular details associated with the physiological roles of GPRC6A.
Results from these experiments revealed that the GPRC6A receptor is not involved in L-arginine-induced insulin release under standard physiological conditions. Further, GPRC6A KO mice display no metabolic phenotype when administered a chow diet, but are susceptible to develop obesity and associated metabolic complications when exposed to an obesogenic environment. Interestingly, chow fed GPRC6A KO mice display an increased drive to voluntary wheel running. Whereas hyperphagia appears to be driving the diet-induced obese (DIO) phenotype, it remains enigmatic how ablation of GPRC6A enhances the drive to exercise. Analyses of plasma parameters identified that DIO GPRC6A KO mice increase glucose, insulin and leptin levels relative to DIO WT mice and that voluntary running increase circulating corticosterone in KO relative to WT mice.
In conclusion, the present thesis provides novel insights into the physiological roles of the GPRC6A receptor. We show that genetic disruption of GPRC6A accelerates the progression of obesity and associated complications when animals are exposed to an obesogenic environment. Additionally, we demonstrate that the GPRC6A receptor is involved in regulating voluntary wheel running, implying that amino acid sensing by GPRC6A impacts energy homeostasis by regulating more than one node within the metabolic network that controls bioenergetics. While these findings broaden our knowledge on the physiological roles of the GPRC6A receptor, more research is warranted to uncover the applied significance of the herein reported findings. Further, illuminating the underlying cellular and molecular mechanisms driving the physiological phenomena reported in this PhD thesis may facilitate the development of novel therapeutic compounds targeting the GPRC6A receptor.