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Osteocalcin-dependent regulation of glucose metabolism and fertility: Skeletal implications for the development of insulin resistance.

Abstract：

:The skeleton has recently emerged as a critical insulin target tissue that regulates whole body glucose metabolism and male reproductive function. While our understanding of these new regulatory axes remains in its infancy, the bone-specific protein, osteocalcin, has been shown to be centrally involved. Undercarboxylated osteocalcin acts as a secretagogue in a feed-forward loop to stimulate pancreatic β-cell proliferation and insulin secretion, improve insulin sensitivity, and promote testosterone production. Importantly, dysregulation of insulin signaling in bone causes a reduction in serum osteocalcin levels that is associated with elevated blood glucose and reduced serum insulin levels, suggesting that the skeleton may play a significant role in the development of diet-induced insulin resistance. Insulin signaling is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1) which becomes hyper-activated in response to nutrient overload. Loss- and gain-of function models suggest that mTORC1 function in bone is essential for normal skeletal development; however, the role of this complex in the regulation of glucose metabolism remains to be determined. This review highlights our current understanding of the role played by osteocalcin in the skeletal regulation of glucose metabolism and fertility. In particular, it examines data emerging from transgenic mouse models which have revealed a pancreas-bone-testis regulatory axis and discusses recent human studies which seek to corroborate findings from mouse models with clinical observations. Moreover, we review recent studies which suggest dysregulation of insulin signaling in bone leads to the development of insulin resistance and discuss the potential role of mTORC1 signaling in this process.

journal_name

J Cell Physiol

journal_title

Journal of cellular physiology

authors

Tangseefa P,Martin SK,Fitter S,Baldock PA,Proud CG,Zannettino ACW

doi

10.1002/jcp.26163

subject

Has Abstract

pub_date

2018-05-01 00:00:00

pages

3769-3783

issue

eissn

0021-9541

issn

1097-4652

journal_volume

233

pub_type

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Osteocalcin-dependent regulation of glucose metabolism and fertility: Skeletal implications for the development of insulin resistance.