Sclerostin has traditionally been thought of as a local inhibitor of bone acquisition that antagonizes the profound osteoanabolic capacity of activated Wnt/β-catenin signaling, but serum sclerostin levels in humans exhibit a correlation with impairments in several metabolic parameters. These data, together with the increased production of sclerostin in mouse models of type 2 diabetes, suggest an endocrine function. To determine whether sclerostin contributes to the coordination of whole-body metabolism, we examined body composition, glucose homeostasis, and fatty acid metabolism in Sost mice as well as mice that overproduce sclerostin as a result of adeno-associated virus expression from the liver. Here, we show that in addition to dramatic increases in bone volume, Sost mice exhibit a reduction in adipose tissue accumulation in association with increased insulin sensitivity. Sclerostin overproduction results in the opposite metabolic phenotype due to adipocyte hypertrophy. Additionally, Sost mice and those administered a sclerostin-neutralizing antibody are resistant to obesogenic diet-induced disturbances in metabolism. This effect appears to be the result of sclerostin's effects on Wnt signaling and metabolism in white adipose tissue. Since adipocytes do not produce sclerostin, these findings suggest an unexplored endocrine function for sclerostin that facilitates communication between the skeleton and adipose tissue.

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 of 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 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 development of a high bone mass phenotype. These data indicate that 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.

The Wnt signaling antagonist, sclerostin, is a potent suppressor of bone acquisition that also mediates endocrine communication between bone and adipose. As a result, Sost −/− mice exhibit dramatic increases in bone formation but marked decreases in visceral and subcutaneous adipose that are secondary to alterations in lipid synthesis and utilization. While interrogating the mechanism by which sclerostin influences adipocyte metabolism, we observed paradoxical increases in the adipogenic potential and numbers of CD45 − :Sca1 + :PDGFRα + adipoprogenitors in the stromal vascular compartment of fat pads isolated from male Sost −/− mice.Lineage tracing studies indicated that sclerostin deficiency blocks the differentiation of PDGFRα + adipoprogenitors to mature adipocytes in association with increased Wnt/β-catenin signaling. Importantly, osteoblast/osteocyte-specific Sost gene deletion mirrors the accumulation of PDGFRα + adipoprogenitors, reduction in fat mass, and improved glucose metabolism evident in Sost −/− mice. These data indicate that bone-derived sclerostin regulates multiple facets of adipocyte physiology ranging from progenitor cell commitment to anabolic metabolism.