Bone Abstracts

We previously elucidated that β-adrenergic blockade attenuates high fat diet induced obesity development and such an effect is associated with suppressed pancreatic lipase (PNLIP) expressions. In the present study, we tested whether β-adrenergic blockade downregulates bioactive osteocalcin secretion in osteoblasts, thereby reduces PNLIP secretion in pancreatic acinar cells.

Forty of male 6wk old C57BL/6 mice were assigned into control diet (CON) and a high calorie diet (HIGH) group. In each diet group, mice were treated with vehicle (VEH) or with propranolol, a β-adrenergic antagonist (BB; 0.5 g/l in drinking water) over 12 weeks.

Expression levels of ESP, a tyrosine phosphatase which downregulates the carboxylation of osteocalcin, in HIGHVEH mice femur were higher vs in CONVEH mice, however, this increment was attenuated by β-blockade in HIGHBB animals. Reductions in serum undercarboxylated bioactive osteocalcin (ucOC) level in HIGHVEH mice was mitigated in HIGHBB mice. In MC3T3E1 osteoblasts, upregulated ESP expression, followed by downregulated osteocalcin expression in isoproterenol, β-adrenergic agonist, treated cells, was attenuated by propranolol treatment. In vitro experiment using primary pancreatic acinar cells and 266-6 cells, pancreatic acinar cell line, PNLIP expressions decreased when the cells were treated with ucOC. ucOC also attenuated isoproterenol induced mouse PNLIP promoter activity. G protein-coupled receptor (GPRC6A), a candidate receptor for mediating the response to ucOC in the bone-pancreas endocrine loop, was highly expressed in mouse pancreatic tissues and in 266-6 cells. Knockdown of GPRC6A by siRNA suppressed downregulating effect of unOC on PNLIP expressions, proposing that GPRC6A mediates responses to osteocalcin in pancreatic acinar cells. In summary, β-adrenergic blockade rescued bioactive osteocalcin secretion in osteoblasts, thereby osteocalcin suppressed PNLIP expressions in pancreatic acinar cells. OCN downregulates PNLIP expressions in GPRC6A mediated manner. These data sheds a light on the crucial endocrine role of the skeleton regulating body energy metabolism.