DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop.
The endocrine role of the skeleton in regulating energy metabolism is supported by a feed-forward loop between circulating osteoblast (OB)-derived undercarboxylated osteocalcin (Glu-OCN) and pancreatic β-cell insulin; in turn, insulin favors osteocalcin (OCN) bioactivity. These data suggest the existence of a negative regulation of this cross talk between OCN and insulin. Recently, we identified delta like-1 (DLK1) as an endocrine regulator of bone turnover. Because DLK1 is colocalized with insulin in pancreatic β-cells, we examined the role of DLK1 in insulin signaling in OBs and energy metabolism. We show that Glu-OCN specifically stimulates Dlk1 expression by the pancreas. Conversely, Dlk1-deficient (Dlk1(-/-) ) mice exhibited increased circulating Glu-OCN levels and increased insulin sensitivity, whereas mice overexpressing Dlk1 in OB displayed reduced insulin secretion and sensitivity due to impaired insulin signaling in OB and lowered Glu-OCN serum levels. Furthermore, Dlk1(-/-) mice treated with Glu-OC experienced significantly lower blood glucose levels than Glu-OCN-treated wild-type mice. The data suggest that Glu-OCN-controlled production of DLK1 by pancreatic β-cells acts as a negative feedback mechanism to counteract the stimulatory effects of insulin on OB production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia.
Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital and University of Southern Denmark, Odense, Denmark babdallah@health.sdu.dk.
Basem M
BM
Abdallah
Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital and University of Southern Denmark, Odense, Denmark.
Nicholas
N
Ditzel
Department of Inorganic and Organic Chemistry and Biochemistry, University of Castilla-La Mancha Medical School, Albacete, Spain.
Jorge
J
Laborda
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY.
Gerard
G
Karsenty
Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital and University of Southern Denmark, Odense, Denmark DanStem (Danish Stem Cell Center), Panum Institute, University of Copenhagen, Copenhagen, Denmark Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Moustapha
M
Kassem
D000818:Animals; D002135:Calcium-Binding Proteins; D025461:Feedback, Physiological; D005947:Glucose / Q000378:metabolism*; D007003:Hypoglycemia / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D010006:Osteoblasts / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D015675:Osteocalcin; D005947:Glucose