The uncovering that leptin regulated bone mass revealed the existence of a control of bone physiology by adipose tissue. Besides the emerging molecular complexity of this regulation its very existence raised a novel question. Do osteoblasts and through them bones regulate in turn expression of leptin and/or of any other adipocyte - derived hormones? To address this question we embarked in a broad-based effort to generate through E.S. cells technology multiple mouse mutant strains each of them lacking one osteoblast enriched gene. We then will analyze their energy metabolism. In the course of there studies we generated through classical and in an osteoblast-specific manner mice lacking Esp. Esp encodes a protein tyrosine phosphatase expressed in osteoblasts and in Sertoli cells of the testis. The only detectable phenotypic abnormalities of any kind one could detect in Esp-deficient mice were an hypoglycemia, an increase in insulin secretion, and an increase in adiponectin secretion resulting in an increase in insulin sensitivity. That these results were obtained in mice lacking this phosphatase only in osteoblasts establishes that bones, through a mechanism we propose to study, regulate energy metabolism. We propose in this application to use a combination of classical physiology, cell-based, molecular, biochemical and genetic approaches to begin elucidating, through Esp biology, this novel function of bones.
The specific aims are: - To demonstrate that the phenotype of Espob-/- mice is due solely to an increase in adiponectin and insulin secretion. - To determine whether Espob-/- mice are resistant to diet induced obesity and type 2 diabetes. - To determine genetically whether Espob-/- mice are resistant to atherosclerosis - To determine whether or not OST-PTP acts through its extracellular domain
|Rached, Marie-Therese; Kode, Aruna; Silva, Barbara C et al. (2010) FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J Clin Invest 120:357-68|
|Ferron, Mathieu; Wei, Jianwen; Yoshizawa, Tatsuya et al. (2010) Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142:296-308|