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

Area of Science:

• Endocrinology and Metabolism
• Cell Biology
• Diabetes Research

Background:

• Loss of functional beta-cell mass is a primary driver of diabetes.
• Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4) is present in human islets, but its role in beta-cell health is unknown.
• Receptor Activator of Nuclear Factor Kappa B (NFκB) (RANK) is a known negative regulator of beta-cell health.

Purpose of the Study:

• To investigate the regulation of Lgr4 in pancreatic islets.
• To determine the role of LGR4 and its interaction with RANK in beta-cell health.
• To assess LGR4 function under basal and stress conditions, both in vitro and in vivo.

Main Methods:

• Evaluated Lgr4 expression in mouse and human islets under various stress conditions (cytokines, high-fat diet, db/db mice, aging).
• Utilized in vitro Lgr4 loss-of-function and gain-of-function studies in primary rodent and human beta-cells.
• Generated beta-cell-specific conditional knockout mice (Lgr4cko and Lgr4/Rank dko) to assess in vivo roles.

Main Results:

• Lgr4 expression decreased under stress; Lgr4 knockdown impaired beta-cell proliferation and survival, while overexpression protected against cell death.
• LGR4 suppresses RANK-TRAF6 interaction, inhibiting NFκB activation and protecting beta-cells.
• Lgr4cko mice showed increased beta-cell death and impaired proliferation/maturation (females), with rescued phenotypes in dko mice and impaired homeostasis in aged Lgr4cko mice.

Conclusions:

• LGR4 acts as a novel positive regulator of beta-cell health under both basal and stress conditions.
• LGR4 exerts its protective effects by antagonizing the detrimental actions of RANK.
• These findings highlight LGR4 as a potential therapeutic target for diabetes.