The class II histone deacetylase HDAC4 regulates cognitive, metabolic and endocrine functions through its expression in osteoblasts.

Objective: The recently described endocrine functions of osteoblasts raise questions about their transcriptional regulation. Thus far, this aspect of osteoblast biology has been addressed only by examining the role of transcription factors binding to specific cis-acting elements in the promoter of the Osteocalcin gene.

Methods: In contrast, the role of chromatin remodeling enzymes, such as histone deacetylases (HDACs), in this process has not as yet been thoroughly understood.

Results: Here we show that through its expression in osteoblasts, one class II HDAC molecule, HDAC4, favors Osteocalcin expression, and as a result, the physiological functions regulated by osteocalcin such as spatial learning, memory, male fertility and insulin secretion. Molecular and genetic evidence indicates that through its expression in osteoblasts HDAC4 fulfills these long-range functions in part by stabilizing the transcription factor ATF4. Remarkably, through its expression in osteoblasts, HDAC4 also enhances appetite, a physiological function that is not regulated by osteocalcin.

Conclusions: These results provide a more in depth molecular understanding of the regulation of the endocrine functions of the osteoblast, and suggest the existence of additional hormones synthesized by osteoblasts that also regulate appetite.