Abstract
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 b-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 b-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 b-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.
| Original language | English |
|---|---|
| Journal | Diabetes |
| Volume | 64 |
| Issue number | 9 |
| Pages (from-to) | 3069-80 |
| Number of pages | 12 |
| ISSN | 0012-1797 |
| DOIs | |
| Publication status | Published - Sept 2015 |
Keywords
- Animals
- Feedback, Physiological
- Glucose
- Hypoglycemia
- Insulin
- Insulin Resistance
- Insulin-Secreting Cells
- Intercellular Signaling Peptides and Proteins
- Mice
- Mice, Knockout
- NIH 3T3 Cells
- Osteoblasts
- Osteocalcin
- RNA, Messenger
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction