Impact of gonadal failure on the bone-mediated regulation of glucose metabolism

The goal of this project is to characterize how gonadal failure may affect the bone-derived hormone osteocalcin and its regulation of β-cell proliferation and function in mice and human. Osteocalcin (Ocn) enhances β-cell proliferation, insulin secretion and insulin sensitivity in adult mice. It is primarily secreted by osteoblasts as an inactive - carboxylated - form, which is released in blood and activated by bone resorption via partial decarboxylation. Hence, physiological or pharmacological events enhancing bone formation and/or resorption should increase blood levels of active Ocn and thereby enhance its positive effect on β-cell mass and glucose metabolism. Gonadal failure is a hallmark of aging that causes major stress to many organs in the body. In particular, bone biology is profoundly affected. Indeed, upon sex steroid hormone depletion like the one accompanying menopause, bone resorption is increased while bone formation does not increase to the same extent. The regulation of Ocn by both bone formation and bone resorption thus raised the prospect that this age-dependent hormonal disruption may affect blood levels of active Ocn and as a result β-cell proliferation and function. In support of this hypothesis, pancreatic cell proliferation in rats is enhanced shortly after ovariectomy (OVX) and our own preliminary results indicate that OVX and orchiectomized (ORCH) mice have 1) higher serum levels of active Ocn, 2) an increase in β-cell mass due to enhanced β-cell proliferation, 3) a mild increase in serum insulin levels and 4) normal blood glucose levels compared to sham-operated (sham) controls. However, β-cell mass and insulin levels are not affected by OVX in Ocn-deficient mice or in Gprc6aPdx1-/- mice and these mice become mildly hyperglycemic 14 days post-surgery. These observations suggest that the effect of estrogen depletion on bone, and on the production of active Ocn, positively impacts β-cell biology. We therefore hypothesize that this regulation could oppose the well- described negative effect of decreased estrogen signaling on β-cell survival and as such preserve, at least transiently, a normal control of glucose metabolism upon gonadal failure. To test this hypothesis we will assess the effect of sex steroid depletion on osteocalcin biology, β-cell biology and glucose metabolism in both mice and humans. Our Specific Aims (SA) are: SA1: To define how estrogen depletion affects the production of active osteocalcin. SA2: To define the Ocn-dependent effects of OVX on β-cell biology and glucose homeostasis. SA3: To determine whether the positive effect of estrogen depletion on osteocalcin biology and its regulation of β-cell proliferation and function is conserved in humans.