Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes

Soohyun P. Kim, Julie L. Frey, Zhu Li, Priyanka Kushwaha, Meredith L. Zoch, Ryan E. Tomlinson, Hao Da, Susan M Aja, Hye Lim Noh, Jason K. Kim, Mehboob Hussain, Daniel L.J. Thorek, Michael J Wolfgang, Ryan Riddle

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E11238-E11247
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number52
DOIs
StatePublished - Dec 26 2017

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Keywords

  • Adipose
  • Bone
  • Metabolism
  • Sclerostin
  • Wnt

ASJC Scopus subject areas

  • General

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