All ETDs from UAB

Advisory Committee Chair

Thomas L Clemens

Advisory Committee Members

Barbara Gower

Ralph D Sanderson

Philip A Wood

Jianhua Zhang

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Insulin and insulin-like growth factor-1 (IGF-1) are evolutionarily conserved hormonal signaling pathways with structurally similar ligands and receptors. Recent stu-dies suggest that that insulin and IGF-1 exert distinct as well as overlapping functions to regulate different aspects of skeletal development. A major problem in distinguishing the actions of insulin and IGF-1 is the fact that the receptors are co-expressed in many cell types and each ligand is able to cross-activate the other ligands' receptor. To distinguish direct skeletal actions of insulin from that of IGF-1, we have conditionally disrupted each receptor in vitro and in vivo specifically in osteoblasts. Studies using osteoblasts lacking the IGF-1R in vitro have allowed us to demonstrate that insulin exerts direct anabolic actions in osteoblasts by activation of its cognate receptor, and that the strength of insulin generated signals is tempered through interactions with IGF-1R. Moreover, insulin treat-ment of ∆IGF-1R osteoblasts rescues the differentiation defect in these cells whereas the differentiation defect in ∆IR osteoblasts cannot be rescued by IGF-1 treatment. To unequivocally establish insulin actions in bone, we have compared the phenotypes of mice which lack either the insulin receptor (Ob-∆IR) or the IGF-1 receptor (Ob-∆IGF-1R) in osteoblasts using a Cre/loxP recombination technique. Mice lacking the IR in osteoblasts failed to accumulate bone primarily due to a reduction in number and/or activity of osteoblasts. By contrast, mice lacking IGF-1R in osteoblasts also had reduced trabecular bone but exhibited normal or even elevated numbers of osteoblasts. The prima-ry defect in these mice was due to a failure to mineralize osteoid matrix. As Ob-∆IR mice aged, they developed features resembling those seen in metabolic syndrome including increased peripheral fat, glucose intolerance, and insulin insensitivity. These changes were accompanied by decreased serum adiponectin. Most importantly, circulating under-carboxylated osteocalcin, a recently identified secretagogue for insulin, was decreased in serum from Ob-∆IR mice. Our findings indicate that insulin signaling regulates postnatal bone acquisition through mechanisms distinct from IGF-1. Moreover, insulin action in osteoblasts also influences fat accumulation, likely by regulating secretion and bioavailability of osteocalcin.

Share

COinS