RRC ID 58589
Author Mizokami A, Mukai S, Gao J, Kawakubo-Yasukochi T, Otani T, Takeuchi H, Jimi E, Hirata M.
Title GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin.
Journal J Endocrinol
Abstract Osteocalcin is a bone-derived hormone that in its uncarboxylated form (GluOC) plays an important role in glucose and energy metabolism by stimulating insulin secretion and pancreatic β-cell proliferation through its putative receptor GPRC6A. We previously showed that the effect of GluOC on insulin secretion is mediated predominantly by glucagon-like peptide-1 (GLP-1) released from intestinal endocrine cells in response to GluOC stimulation. Moreover, oral administration of GluOC was found to reduce the fasting blood glucose level, to improve glucose tolerance, and to increase the fasting serum insulin concentration and β-cell area in the pancreas in wild-type mice. We have now examined the effects of oral GluOC administration for at least 4 weeks in GLP-1 receptor-knockout mice. Such administration of GluOC in the mutant mice triggered glucose intolerance, enhanced gluconeogenesis and promoted both lipid accumulation in the liver as well as adipocyte hypertrophy and inflammation in adipose tissue. Furthermore, inactivation of GLP-1 receptor signaling in association with GluOC administration induced activation of the transcription factor FoxO1 and expression of its transcriptional coactivator PGC1α in the liver, likely accounting for the observed upregulation of gluconeogenic gene expression. Our results thus indicate that the beneficial metabolic effects of GluOC are dependent on GLP-1 receptor signaling.
Volume 244(2)
Pages 285-296
Published 2020-2-1
DOI 10.1530/JOE-19-0288
PII JOE-19-0288.R1
PMID 31693486
MeSH Animals Blood Glucose / metabolism Female Forkhead Box Protein O1 / genetics Forkhead Box Protein O1 / metabolism Glucagon-Like Peptide 1 / genetics Glucagon-Like Peptide 1 / metabolism* Glucose Intolerance / genetics Glucose Intolerance / metabolism* Glucose Tolerance Test Humans Insulin / metabolism Insulin-Secreting Cells / metabolism Kidney / metabolism Liver / metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Osteocalcin / metabolism* Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism Receptors, Glucagon / genetics Receptors, Glucagon / metabolism
IF 4.381
Times Cited 1
Human and Animal Cells Hepa 1-6(RCB1638)