Sclerostin exerts profound local control over bone acquisition and also mediates endocrine communication between fat and bone. In bone, sclerostin’s anti-osteoanabolic activity is enhanced by low-density lipoprotein receptor-related protein-4 (Lrp4), which facilitates its interaction with the Lrp5 and Lrp6 Wnt co-receptors. To determine whether Lrp4 similarly affects sclerostin’s endocrine function, we examined body composition as well as glucose and fatty acid metabolism in mice rendered deficient for Lrp4 in the adipocyte (Ad¿Lrp4) or the osteoblast (Ob¿Lrp4). Ad¿Lrp4 mice exhibit a reduction in adipocyte hypertrophy and improved glucose and lipid homeostasis, marked by increased glucose and insulin tolerance and reduced serum fatty acids, and thereby mirror the effect of sclerostin-deficiency on whole-body metabolism. Indeed, epistasis studies place adipocyte-expressed Lrp4 and sclerostin in the same genetic cascade that regulates adipocyte function. Intriguingly, Ob¿Lrp4 mice, which exhibit dramatic increases in serum sclerostin, accumulate body fat and develop impairments in glucose tolerance and insulin sensitivity, despite the development of a high bone mass phenotype. These data indicated that the expression of Lrp4 by both the adipocyte and osteoblast is required for normal sclerostin endocrine function and that the impact of sclerostin deficiency on adipocyte physiology is distinct from the effect on osteoblast function.

Read more »