FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice
Marie-Therese Rached, Aruna Kode, Barbara C. Silva, Dae Young Jung, Susan Gray, Helena Ong, Ji-Hye Paik, Ronald A. DePinho, Jason K. Kim, Gerard Karsenty, Stavroula Kousteni
Marie-Therese Rached, Aruna Kode, Barbara C. Silva, Dae Young Jung, Susan Gray, Helena Ong, Ji-Hye Paik, Ronald A. DePinho, Jason K. Kim, Gerard Karsenty, Stavroula Kousteni
View: Text | PDF | Corrigendum
Research Article

FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice

Abstract

Osteoblasts have recently been found to play a role in regulating glucose metabolism through secretion of osteocalcin. It is unknown, however, how this osteoblast function is regulated transcriptionally. As FoxO1 is a forkhead family transcription factor known to regulate several key aspects of glucose homeostasis, we investigated whether its expression in osteoblasts may contribute to its metabolic functions. Here we show that mice lacking Foxo1 only in osteoblasts had increased pancreatic β cell proliferation, insulin secretion, and insulin sensitivity. The ability of osteoblast-specific FoxO1 deficiency to affect metabolic homeostasis was due to increased osteocalcin expression and decreased expression of Esp, a gene that encodes a protein responsible for decreasing the bioactivity of osteocalcin. These results indicate that FoxO1 expression in osteoblasts contributes to FoxO1 control of glucose homeostasis and identify FoxO1 as a key modulator of the ability of the skeleton to function as an endocrine organ regulating glucose metabolism.

Authors

Marie-Therese Rached, Aruna Kode, Barbara C. Silva, Dae Young Jung, Susan Gray, Helena Ong, Ji-Hye Paik, Ronald A. DePinho, Jason K. Kim, Gerard Karsenty, Stavroula Kousteni

×

Figure 2

Increased β cell proliferation and insulin secretion in Foxo1ob–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Increased β cell proliferation and insulin secretion in Foxo1ob–/– mice....
(A) Blood glucose levels in WT and Foxo1ob–/– newborn before milk ingestion; n = 5 pups. (B) Blood glucose and (C) serum insulin levels in WT and Foxo1ob–/– mice at random feeding; n = 5. (D) Plasma insulin levels after glucose injection in WT and Foxo1ob–/– mice; n = 4/group. (E) H&E and insulin staining and (F) Ki67 immunostaining showing larger islets and increased β cell proliferation in the pancreas of Foxo1ob–/– mice; n = 5 mice/group. Scale bars represent 100 μm, except in the H&E panels, where they represent 800 μm. (G) Fasting blood glucose levels in WT and Foxo1ob–/– adult mice; n = 5 mice/group. (H) GTT in WT and Foxo1ob–/– mice; n = 5 mice/ group. (I) PTTs in WT and Foxo1ob–/– mice; n = 5 mice/group. In all panels, data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by Student’s t test. In B–I, all mice were 2 months of age.