Osteocalcin-dependent regulation of glucose metabolism and fertility: Skeletal implications for the development of insulin resistance
| Autor: | Stephen Fitter, Andrew C.W. Zannettino, Sally Martin, Christopher G. Proud, Pawanrat Tangseefa, Paul A. Baldock |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genetically modified mouse medicine.medical_specialty Physiology medicine.medical_treatment Clinical Biochemistry Osteocalcin mTORC1 Carbohydrate metabolism Biology 03 medical and health sciences Insulin resistance Internal medicine medicine Animals Humans Muscle Skeletal Insulin Cell Biology medicine.disease Insulin receptor 030104 developmental biology Endocrinology Fertility Glucose biology.protein Secretagogue Insulin Resistance Energy Metabolism |
| Zdroj: | Journal of cellular physiology. 233(5) |
| ISSN: | 1097-4652 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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