Sex- and bone-specific responses in bone structure to exogenous leptin and leptin receptor antagonism in the ovine fetus

Abstract

Widespread expression of leptin and its receptor in developing cartilage and bone suggests that leptin may regulate bone growth and development in the fetus. Using microcomputed tomography, this study investigated the effects of exogenous leptin and leptin receptor antagonism on aspects of bone structure in the sheep fetus during late gestation. From 125 to 130 days of gestation (term ~145 days), chronically catheterized singleton sheep fetuses were infused intravenously for 5 days with either saline (0.9% saline, n = 13), recombinant ovine leptin at two doses (0.6 mg·kg·day LEP1, n = 10 or 1.4 mg·kg·day LEP2, n = 7), or recombinant superactive ovine leptin receptor antagonist (4.6 mg·kg·day SOLA, n = 6). No significant differences in plasma insulin-like growth factor-I, osteocalcin, calcium, inorganic phosphate, or alkaline phosphatase were observed between treatment groups. Total femur midshaft diameter and metatarsal lumen diameter were narrower in male fetuses treated with exogenous leptin. In a fixed length of femur midshaft, total and bone volumes were reduced by the higher dose of leptin; nonbone space volume was lower in both groups of leptin-treated fetuses. Leptin infusion caused increments in femur porosity and connectivity density, and vertebral trabecular thickness. Leptin receptor antagonism decreased trabecular spacing and increased trabecular number, degree of anisotrophy, and connectivity density in the lumbar vertebrae. The increase in vertebral porosity observed following leptin receptor antagonism was greater in the malecompared with female, fetuses. Therefore, leptin may have a role in the growth and development of the fetal skeleton, dependent on the concentration of leptin, sex of the fetus, and bone type examined.

Pancreas deficiency modifies bone development in the ovine fetus near term

“…Like insulin, leptin has been proposed as a mechanism linking bone remodelling with nutrient availability before and after birth ( Forhead & Fowden 2009 , Devlin & Bouxsein 2012 ), and a relationship between circulating insulin and adipose leptin mRNA has been shown previously in fetal sheep ( Devaskar et al 2002 ). Infusion of supraphysiological concentrations of leptin influences metatarsal Tb structure in fetal sheep, although leptin receptor antagonism only affected the development of the vertebra, and not the metatarsal or femur ( De Blasio et al 2018 ). Further studies are required to determine the effects of intrauterine pancreas deficiency on leptin signalling within the developing skeleton and to assess the relative contribution of low circulating leptin on bone structure and function in this model.…”