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

Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11238-E11247. doi: 10.1073/pnas.1707876115. Epub 2017 Dec 11.

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.

Keywords: Wnt; adipose; bone; metabolism; sclerostin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adipocytes / metabolism*
  • Adipocytes / pathology
  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology
  • Animals
  • Body Composition*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Wnt Signaling Pathway*

Substances

  • Adaptor Proteins, Signal Transducing
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Sost protein, mouse