LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity.

Summary

Across human genetics, Mendelian randomization, and adipose cell experiments, LRP5 was shown to drive lower-body fat distribution and enhance systemic/adipocyte insulin sensitivity independent of bone effects. Mechanistically, LRP5 supports adipose progenitor function via WNT/β-catenin signaling and VCP-mediated proteostasis and protects against age-related lower-body fat loss.

Key Findings

• LRP5 promotes lower-body fat distribution and increases systemic and adipocyte insulin sensitivity independent of bone effects.
• LRP5 maintains adipose progenitor cell fitness via WNT/β-catenin signaling and VCP-mediated proteostasis.
• Gain-of-function LRP5 variants protect against age-related loss of lower-body fat; LRP5 expression in adipose progenitors declines with age.

Clinical Implications

While not practice-changing yet, the work supports developing adipose-selective LRP5/WNT modulators to preserve lower-body fat and improve insulin sensitivity, potentially preventing metabolic syndrome and age-related fat redistribution.

Limitations

• Non-randomized translational design; causal inference for clinical outcomes remains indirect
• Sample sizes and population diversity for human mutation carriers may limit generalizability; therapeutic modulation safety unknown

Future Directions

Develop adipose-targeted LRP5/WNT modulators, validate effects in diverse populations, and test metabolic outcomes in early-phase clinical trials.