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
Proposed model of DLK1 action in regulating the OCN-insulin feed-forward loop.
OB-secreted Glu-OCN stimulates DLK1 production by islet β-cells. DLK1 exerts a negative feedback mechanism that impairs insulin signaling–induced OCN production by OB, thus antagonizing Glu-OCN–induced hypoglycemia. P, phosphorylation.
