Osteoprotegerin/Receptor Activator of Nuclear Factor-Kappa B Ligand/Receptor Activator of Nuclear Factor-Kappa B Axis in Obesity, Type 2 Diabetes Mellitus, and Nonalcoholic Fatty Liver Disease

Purpose of ReviewTo summarize evidence on the potential involvement of the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B (NF-kappa Beta) ligand (RANKL)/receptor activator of NF-kappa Beta (RANK) axis in the pathogenesis of metabolic diseases.Recent FindingsThe OPG-RANKL-RANK axis, which has been originally involved in bone remodeling and osteoporosis, is now recognized as a potential contributor in the pathogenesis of obesity and its associated comorbidities, i.e., type 2 diabetes mellitus and nonalcoholic fatty liver disease. Besides bone, OPG and RANKL are also produced in adipose tissue and may be involved in the inflammatory process associated with obesity. Metabolically healthy obesity has been associated with lower circulating OPG concentrations, possibly representing a counteracting mechanism, while elevated serum OPG levels may reflect an increased risk of metabolic dysfunction or cardiovascular disease. OPG and RANKL have been also proposed as potential regulators of glucose metabolism and are potentially involved in the pathogenesis of type 2 diabetes mellitus. In clinical terms, type 2 diabetes mellitus has been consistently associated with increased serum OPG concentrations. With regard to nonalcoholic fatty liver disease, experimental data suggest a potential contribution of OPG and RANKL in hepatic steatosis, inflammation, and fibrosis; however, most clinical studies showed reduction in serum concentrations of OPG and RANKL.SummaryThe emerging contribution of the OPG-RANKL-RANK axis to the pathogenesis of obesity and its associated comorbidities warrants further investigation by mechanistic studies and may have potential diagnostic and therapeutic implications.

Automated summary

The purpose of this review is to summarize the evidence on the potential involvement of the OPG/RANKL/RANK axis in the pathogenesis of metabolic diseases. Recent findings suggest that this axis, originally associated with bone remodeling and osteoporosis, may also play a role in obesity and its associated comorbidities such as type 2 diabetes mellitus and nonalcoholic fatty liver disease. OPG and RANKL are produced in adipose tissue and may be involved in the inflammatory process associated with obesity. Clinical studies have shown associations between OPG and RANKL levels and metabolic dysfunction. Further investigation is needed to understand the mechanisms and potential therapeutic implications of this axis.