Osteocalcin: An Endocrine Link Between Bone and Glucose Metabolism

Bu B Yeap


Expert Rev Endocrinol Metab. 2011;6(2):177-185. 

In This Article

Osteocalcin as a Novel Regulator of Insulin Secretion & Insulin Sensitivity

In humans, as in mice, osteocalcin is a bone matrix protein also present in the circulation.[19,20] Osteocalcin has 49 amino acids and undergoes γ-carboxylation of glutamyl residues at positions 17, 21 and 24, which facilitates binding of osteocalcin to hydroxyapatite in bone (Figure 2). The process of γ-carboxylation is vitamin K dependent. Circulating total osteocalcin (TOC), which has been assayed as a marker of bone turnover, comprises both γ-carboxylated osteocalcin and undercarboxylated osteocalcin (ucOC). Interestingly, homozygous Ocn-knockout mice (Ocn−/−) do not display an abnormal bone phenotype despite its presence in the bone matrix.[17] However, later in life, Ocn−/− mice become glucose intolerant and obese. Ocn−/− mice exhibit reduced pancreatic β-cell mass and insulin content, reduced expression of adiponectin in adipose tissue and reduced circulating adiponectin (Figure 1C). Finally, administration of osteocalcin to mice resulted in insulin-sensitizing effects.[17]

Figure 2.

Both undercarboxylated and γ-carboxylated osteocalcin are present in the circulation. (A) Human osteocalcin is a 49 amino acid peptide with glutamate residues at positions 17, 21 and 24, which can be γ-carboxylated. (B) Lability at the C-terminus results in a major fragment of 43 amino acids. (C) Carboxylated osteocalcin has greater binding affinity to hydroxyapatite in vivo (to bone) and in vitro (allowing assay of unbound undercarboxylated osteocalcin).

Although deletion of Ocn reversed the insulin-sensitive phenotype of Esp−/− mice, they had similar circulating TOC as wild-type controls.[17] However, a higher proportion of their circulating osteocalcin was lacking γ-carboxylation. This was reflected by reduced binding of serum osteocalcin to hydroxyapatite in vitro. Consistent with these findings, in cell culture studies, treatment with ucOC resulted in increased β-cell expression of insulin and adipocyte expression of adiponectin – effects not seen following treatment with fully carboxylated osteocalcin.[17] Furthermore, administration of exogenous ucOC to wild-type mice increased expression of insulin by β-cells and adiponectin by adipocytes, and increased both serum insulin levels and insulin sensitivity.[21] Thus, ucOC was the metabolically active form of osteocalcin (Figure 2). These findings have been hailed as a new and vitally important paradigm in the regulation of energy metabolism, with ucOC representing a novel endocrine stimulator of insulin and adiponectin secretion.[22]


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