DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop
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DLK1 Regulates Whole-Body Glucose Metabolism : A Negative Feedback Regulation of the Osteocalcin-Insulin Loop. / Abdallah, Basem M; Ditzel, Nicholas; Laborda, Jorge; Karsenty, Gerard; Kassem, Moustapha.
I: Diabetes, Bind 64, Nr. 9, 09.2015, s. 3069-80.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - DLK1 Regulates Whole-Body Glucose Metabolism
T2 - A Negative Feedback Regulation of the Osteocalcin-Insulin Loop
AU - Abdallah, Basem M
AU - Ditzel, Nicholas
AU - Laborda, Jorge
AU - Karsenty, Gerard
AU - Kassem, Moustapha
N1 - © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
PY - 2015/9
Y1 - 2015/9
N2 - 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.
AB - 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.
KW - Animals
KW - Feedback, Physiological
KW - Glucose
KW - Hypoglycemia
KW - Insulin
KW - Insulin Resistance
KW - Insulin-Secreting Cells
KW - Intercellular Signaling Peptides and Proteins
KW - Mice
KW - Mice, Knockout
KW - NIH 3T3 Cells
KW - Osteoblasts
KW - Osteocalcin
KW - RNA, Messenger
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Signal Transduction
U2 - 10.2337/db14-1642
DO - 10.2337/db14-1642
M3 - Journal article
C2 - 25918236
VL - 64
SP - 3069
EP - 3080
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 9
ER -
ID: 160408183