Osteocyte-Secreted Wnt Signaling Inhibitor Sclerostin Contributes to Beige Adipogenesis in Peripheral Fat Depots

Abstract

Cells of the osteoblast lineage are increasingly identified as participants in whole-body metabolism by primarily targeting pancreatic insulin secretion or consuming energy. Osteocytes, the most abundant bone cells, secrete a Wnt-signaling inhibitor called sclerostin. Here we examined three mouse models expressing high sclerostin levels, achieved through constitutive or inducible loss of the stimulatory subunit of G-proteins (Gsα in mature osteoblasts and/or osteocytes). These mice showed progressive loss of white adipose tissue (WAT) with tendency toward increased energy expenditure but no changes in glucose or insulin metabolism. Interestingly beige adipocytes were increased extensively in both gonadal and inguinal WAT and had reduced canonical β-catenin signaling. To determine if sclerostin directly contributes to the increased beige adipogenesis, we engineered an osteocytic cell line lacking Gsα which has high sclerostin secretion. Conditioned media from these cells significantly increased expression of UCP1 in primary adipocytes, and this effect was partially reduced after depletion of sclerostin from the conditioned media. Similarly, treatment of Gsα-deficient animals with sclerostin-neutralizing antibody partially reduced the increased UCP1 expression in WAT. Moreover, direct treatment of sclerostin to wild-type mice significantly increased UCP1 expression in WAT. These results show that osteocytes and/or osteoblasts secrete factors regulating beige adipogenesis, at least in part, through the Wnt-signaling inhibitor sclerostin. Further studies are needed to assess metabolic effects of sclerostin on adipocytes and other metabolic tissues.

Osteocyte Mechanobiology

“…Communication between adjacent osteocytes and neighboring cells is mediated by gap junctions. In addition, osteocytes can signal to distant cells or organs via secreted factors released in the bone marrow space or directly into the circulation (8). Their location, deeply into the mineralized bone, and their structural organization of a cellular network, make them ideal to sense mechanical stimuli and to transduce these signals into biochemical cues affecting the surrounding cells.…”

Ex Vivo Organ Cultures as Models to Study Bone Biology

“…Our group recently started to use ex vivo fat and pancreas organ cultures to investigate the cross‐talk between bone and fat, and bone and pancreas. Growing evidence suggests that bone‐derived sclerostin regulates body composition and glucose metabolism . We found that mice with elevated circulating sclerostin exhibit increased peripheral white fat mass and upregulation of genes involved in mitochondrial respiration and biogenesis including Pgc1α, Ucp1, or Prdm16.…”

“…The skeleton is emerging as an important endocrine organ implicated in the regulation of whole‐body composition and glucose metabolism . Similarly, bone and muscle communication has been a major focus of musculoskeletal research in the recent years .…”

Circulating molecules that control brown/beige adipocyte differentiation and thermogenic capacity

“…Bone‐derived factors also play a role in browning. The osteocyte‐secreted factor sclerostin , normally associated with osteoporosis, contributes to increased beige adipogenesis in vivo and in vitro (Fulzele et al, ). To demonstrate the effect of sclerostin, Fulzele et al engineered an osteocytic cell line lacking Gsα to express and secrete high levels of sclerostin.…”