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

被引:187
作者
Rached, Marie-Therese [1 ]
Kode, Aruna [1 ]
Silva, Barbara C. [1 ]
Jung, Dae Young [2 ]
Gray, Susan [2 ]
Ong, Helena [2 ]
Paik, Ji-Hye [3 ,4 ]
DePinho, Ronald A. [3 ,4 ]
Kim, Jason K. [2 ,5 ]
Karsenty, Gerard [6 ]
Kousteni, Stavroula [1 ]
机构
[1] Columbia Univ, Coll Phys & Surg, Dept Med, Div Endocrinol, New York, NY USA
[2] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA
[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[4] Dana Farber Canc Inst, Ctr Appl Canc Sci, Boston, MA 02115 USA
[5] Univ Massachusetts, Sch Med, Dept Med, Div Endocrinol Metab & Diabet, Worcester, MA USA
[6] Columbia Univ, Coll Phys & Surg, Dept Genet & Dev, New York, NY USA
关键词
TRANSCRIPTION FACTOR FOXO1; BETA-CELL; CAENORHABDITIS-ELEGANS; TRANSGENIC MICE; INSULIN ACTION; DIABETES-MELLITUS; SIGNALING PATHWAY; OXIDATIVE STRESS; GLYCEMIC CONTROL; GENE-EXPRESSION;
D O I
10.1172/JCI39901
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 beta 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.
引用
收藏
页码:357 / 368
页数:12
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