# Adipocytic sclerostin loop3-LRP4 interaction required by sclerostin to impair whole-body lipid and glucose metabolism

## TL;DR

The study shows that a specific interaction involving sclerostin helps impair lipid and glucose metabolism, and blocking this interaction could improve metabolic issues in osteoporosis patients with diabetes.

## Contribution

The study identifies the role of the adipocytic sclerostin loop3-LRP4 interaction in impairing lipid and glucose metabolism and proposes a novel therapeutic strategy to block this interaction.

## Key findings

- Elevated serum sclerostin levels are observed in postmenopausal osteoporosis and newly-diagnosed T2DM patients.
- Blocking the adipocytic sclerostin loop3-LRP4 interaction attenuates the impairment of lipid and glucose metabolism.
- The study proposes a new strategy to normalize metabolism in osteoporosis-diabetes patients by targeting this interaction.

## Abstract

Sclerostin, which has three loops, inhibits bone formation and impairs whole-body lipid and glucose metabolism. The marketed therapeutic sclerostin antibody for postmenopausal osteoporosis (POP) mainly targeting loop2 promotes bone formation and improves whole-body lipid and glucose metabolism. However, FDA/EMA warns of its cardiovascular risk. We previously demonstrate that sclerostin loop3 contributes to the inhibitory effect of sclerostin on bone formation but not its cardioprotective effect. Here we find elevated serum sclerostin levels in both POP-T2DM patients and newly-diagnosed T2DM patients and further demonstrate that sclerostin loop3 participates in the impairment effect of sclerostin on whole-body lipid and glucose metabolism in vivo. Mechanistically, specific blockade of adipocytic sclerostin loop3-LRP4 interaction attenuates the impairment effect of sclerostin on lipid and glucose metabolism in vitro and in vivo. This study provides an innovative strategy, blocking adipocytic sclerostin loop3-LRP4 interaction, to normalize lipid and glucose metabolism in POP-T2DM patients, in cardiovascular safety.

Sclerostin impairs whole-body lipidandglucosemetabolism. Here, the authors further demonstrate that adipocytic sclerostin loop3-LRP4 interactionparticipatesin the impairment effect of sclerostin on whole-body lipid and glucose metabolism.