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
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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

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Figure 3

Increased insulin sensitivity in Foxo1ob–/– mice.

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Increased insulin sensitivity in Foxo1ob–/– mice. (A) ITTs in WT and...
(A) ITTs in WT and Foxo1ob–/– mice; n = 5 mice/group. (Identical data are shown in Figure 5E.) (B) Glucose infusion rate (GIR) and suppression of hepatic glucose production (HGP) (% of clamp HGP relative to basal HGP) in WT (n = 3) and Foxo1ob–/– (n = 5) mice by hyperinsulinemic-euglycemic clamps. (C) Real-time PCR analysis of insulin target gene expression in skeletal muscle of WT and Foxo1ob–/– mice. Values are expressed as fold increase relative to WT; n = 4 mice/group. (D and E) HPLC analysis of adenine nucleotide levels in the vastus lateralis muscle; n = 4 mice/group. (F) Real-time PCR analysis of insulin target genes in the liver of WT and Foxo1ob–/– mice; n = 4 mice/group. (G) Oil red O staining in liver sections of WT and Foxo1ob–/– mice; n = 4 mice/group. Scale bars: 100 μm. In all panels, data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by Student’s t test. All mice were 2–3 months of age.