Sclerostin deficiency sensitizes white adipocytes to thermogenic signals that induce beiging in mice

Maintenance of bone mass is coordinated with adipose tissue function through the secretion of hormones and endocrine factors that act on the opposing tissue. Sclerostin, a small glycoprotein produced by osteocytes embedded within the bone matrix, potently suppresses bone formation by antagonizing Wnt/β-catenin signaling while stimulating adipose tissue accumulation via the same mechanism of action. Since sclerostin-deficient mice develop pockets of multilocular adipocytes in subcutaneous adipose, we investigate the influence of sclerostin on thermogenic and β3-adrenergic stimuli-induced white adipose tissue beiging. Here, we report that Sost gene expression in bone and serum sclerostin levels are induced by β3-adrenergic agonists via an adipose-to-bone relay. Gene knockout studies suggest sclerostin acts to inhibit adipose tissue beiging by modulating β-catenin, as male Sost-/- mice display a greater abundance of beige adipocytes after chronic treatment with CL316,243 or cold exposure. Likewise, housing at thermoneutrality is sufficient to eliminate the decrease in fat mass and increased insulin sensitivity evident in sclerostin mutants under standard conditions. We also demonstrate that co-administration of a β3-adrenergic agonist and a sclerostin neutralizing antibody synergistically influences metabolic parameters in a mouse obesity model. These data suggest utility in interrogating this interaction in the treatment of metabolic disorders. This manuscript from Choquette and colleagues finds that sclerostin gene expression is up-regulated in bone by β3-adrenergic signaling via an adipose to bone relay and acts as an endocrine factor to inhibit adipose tissue beiging in mice.