Adipocytic sclerostin loop3-LRP4 interaction required by sclerostin to impair whole-body lipid and glucose metabolism.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41545413.
- Also identified by DOI 10.1038/s41467-026-68526-w and PMC identifier 12917164.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Adaptor Proteins, Signal Transducing
- Glucose
- Lipid Metabolism
- Diabetes Mellitus, Type 2
- Adipocytes