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Osteocalcin in the brain: from embryonic development to age-related decline in cognition

Key Points

  • Undercarboxylated osteocalcin regulates anxiety and cognition in adult mice

  • Osteocalcin is necessary and sufficient to correct age-related decline in cognitive function in mice

  • Mouse maternal osteocalcin contributes to brain development and the acquisition of cognitive function in the fetus starting at embryonic day (E) 14.5

  • Probable G protein-coupled receptor 158 (GPR158) regulates the role of osteocalcin in anxiety and cognition in the mouse brain

Abstract

A remarkable, unexpected aspect of the bone-derived hormone osteocalcin is that it is necessary for both brain development and brain function in the mouse, as its absence results in a profound deficit in spatial learning and memory and an exacerbation of anxiety-like behaviour. The regulation of cognitive function by osteocalcin, together with the fact that its circulating levels decrease in midlife compared with adolescence in all species tested, raised the prospect that osteocalcin might be an anti-geronic hormone that could prevent age-related cognitive decline. As presented in this Review, recent data indicate that this is indeed the case and that osteocalcin is necessary for the anti-geronic activity recently ascribed to the plasma of young wild-type mice. The diversity and amplitude of the functions of osteocalcin in the brain, during development and postnatally, had long called for the identification of its receptor in the brain, which was also recently achieved. This Review presents our current understanding of the biology of osteocalcin in the brain, highlighting the bony vertebrate specificity of the regulation of cognitive function and pointing toward where therapeutic opportunities might exist.

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Figure 1: Osteocalcin functions in peripheral organs.
Figure 2: Undercarboxylated osteocalcin promotes spatial learning and memory and prevents anxiety-like behaviour.
Figure 3: Maternal undercarboxylated osteocalcin acts directly in the offspring to regulate embryonic brain development.
Figure 4: Osteocalcin is sufficient to improve cognition in aged mice.
Figure 5: Probable G protein-coupled receptor 158 mediates the functions of osteocalcin in the mouse brain.

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Acknowledgements

This work was supported by 2P01 AG032959-06A1 and the Columbia Aging Center (G.K.), a 5T32DK007328-38 Endocrinology Training Grant (L.K.) from the NIH, Fondation pour la Recherche Medicale grant AJE20130928594, the Human Frontier Scientific Program–Grant ATIP-AVENIR INSERM - R14080KS - RSE15007KSA Program–INSERM, Grant AGEMED-INSERM (F.O.) and the Philippe Foundation (A.O.).

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A.O., L.K., G.K. and F.O. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Gerard Karsenty or Franck Oury.

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Obri, A., Khrimian, L., Karsenty, G. et al. Osteocalcin in the brain: from embryonic development to age-related decline in cognition. Nat Rev Endocrinol 14, 174–182 (2018). https://doi.org/10.1038/nrendo.2017.181

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