What question did this study set out to answer?

This research aims to understand how sclerostin deficiency affects the ability of white adipocytes to adapt to thermogenic signals.

February 8, 2026Open Access

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

Key Points

This research aims to understand how sclerostin deficiency affects the ability of white adipocytes to adapt to thermogenic signals.
Investigated gene expression of sclerostin in response to β3-adrenergic stimuli
Conducted knockout studies on Sost gene in mice
Administered β3-adrenergic agonist and sclerostin neutralizing antibody in a mouse obesity model
Evaluated thermogenic responses in sclerostin-deficient mice under varying conditions
Sost gene expression and serum sclerostin levels increase with β3-adrenergic agonists
Sost-/- mice show a higher abundance of beige adipocytes after cold exposure or treatment with CL316,243
Chronic treatments lead to lower fat mass and improved insulin sensitivity in mutant mice
Co-administration of β3-adrenergic agonist and sclerostin neutralizing antibody shows positive effects on metabolism in obesity model.

Abstract

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.

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