Selective β3 Adrenergic Receptor Agonist CL316,243 Increases the Blood Concentrations of Free Fatty Acids and GDF15

β3 adrenergic receptor (β3AR) agonists were originally developed to overcome obesity. Administration of selective β3AR agonist CL316,243 induces lipolysis and elevates the blood concentrations of growth differentiation factor 15 (GDF15), which exerts appetite-suppressing effects in mice. Liver is the main source of GDF15 in the circulation; however, it does not express β3AR. In this study, we hypothesized that free fatty acids (FFAs) released into the circulation upon lipolysis by the β3AR agonist induce GDF15 secretion from the liver. To verify this hypothesis, we manipulated the adiposity of mice using two different models, diet-induced obesity and surgical removal of white adipose tissue models, and measured the blood FFA and GDF15 levels after CL316,243 administration. Sustained elevation of blood FFA levels correlated with elevated blood GDF15 levels in the diet-induced obesity model. Conversely, surgical removal of white adipose tissue reduced the blood concentrations of FFAs and GDF15 after CL316,243 administration. Notably, CL316,243 failed to induce Gdf15 expression in AML12 mouse hepatocytes. However, FFAs induced Gdf15 expression in AML12 cells, with stearic acid acting as the most potent FFA. These data suggest that FFAs released via β3AR agonist-induced lipolysis increase Gdf15 expression levels in the liver and elevate blood GDF15 concentrations in mice. The sustained elevation of blood GDF15 levels in obese model mice by the β3AR agonist possibly reduced appetite more effectively in the obesity state than in the lean state.