In the past decade, multiple studies have revealed that osteoblast-derived hormone osteocalcin, in its uncarboxylated form (GluOC), could reverse the diabetic conditions by affecting multiple aspects of systemic glucose and energy metabolism, male fertility, and brain function. Metabolic effects of GluOC are primarily achieved by its ability to stimulate insulin secretion and pancreatic β-cell proliferation either directly, or indirectly through stimulating the secretion of glucagon-like peptide-1 (GLP-1) from intestinal endocrine cells through its putative receptor GPRC6A. We have previously reported that oral administration of GluOC, the most common and safe route of drug administration, reduced the fasting blood glucose level, improved glucose tolerance, and increased the fasting serum insulin concentration as well as the β-cell area in the pancreas in wild type mice. However, these effects were abolished by the prior subcutaneous administration of exendin (9-39), a GLP-1 receptor antagonistic peptide, suggestive of the requirement of GLP-1 receptor signaling for orally-administered GluOC effects. In this study, we examined the effect of GluOC using GLP-1 receptor-knockout mice to explore the involvement of GLP-1 receptor signaling in the GluOC-mediated improvement of glucose handling. We found that long-term oral administration of GluOC rather triggered glucose intolerance, enhanced gluconeogenesis, lipid accumulation in the liver, and adipocyte hypertrophy in GLP-1 receptor-knockout mice. Furthermore, we revealed that inactivation of GLP-1 receptor signaling in association with GluOC promotes FoxO1 action, leading to gluconeogenesis. These results indicate that the beneficial effect of GluOC on glucose and lipid metabolism is dependent on functional GLP-1 receptor signaling.
A. Mizokami: None. M. Hirata: None.
Japan Society for the Promotion of Science (16K20421, 17K19766)