LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK

Area of Science:

• Endocrinology and Metabolism
• Cell Biology
• Diabetes Research

Background:

• Pancreatic beta-cell dysfunction and stress are key drivers of diabetes progression.
• Leucine-rich repeat-containing G-protein-coupled-receptor-4 (LGR4) role in beta-cell health is under investigation.
• Understanding LGR4's function is critical for developing novel diabetes therapies.

Approach:

• Investigated LGR4's role in rodent and human beta-cells using in vitro knockdown and overexpression models.
• Utilized Lgr4-conditional knockout mice (Lgr4 cko) to study its function in vivo under basal, stress, and aging conditions.
• Examined the molecular mechanism involving Receptor Activator of Nuclear Factor Kappa B (NFκB) (RANK) signaling pathway.

Key Points:

• LGR4 is essential for beta-cell proliferation and survival, both in vitro and in vivo.
• LGR4 protects beta-cells from cytokine-induced death by suppressing RANK and NFκB activation.
• Lgr4 cko mice show impaired beta-cell homeostasis, increased death, and altered proliferation, particularly under stress and aging.
• Female Lgr4 cko mice exhibit glucose intolerance and decreased insulin levels with aging.

Conclusions:

• LGR4 is a critical regulator of pancreatic beta-cell health under both basal and stress-induced conditions.
• LGR4's protective mechanism involves the suppression of the RANK/NFκB pathway.
• Targeting LGR4 may offer a therapeutic strategy for managing diabetes by preserving beta-cell function.