Endocrine Abstracts

Bile acids (BAs) are synthesised from cholesterol in the liver and promote lipid digestion. An emerging body of evidence, however, suggests that BAs are also key signaling molecules with potent metabolic and endocrine functions, exerting their effects through activation of BA receptors, including the farnesoid-X- (FXR) and the G-protein-coupled- (TGR5) receptors. Disturbed BA synthesis has been associated with type 2 diabetes mellitus and insulin resistance, and recent studies have revealed expression of BA receptors in adipose tissue. However, the potential role of BAs to regulate human adiposity is poorly described. We have hypothesised that BAs play an important role in human adipose tissue differentiation and function. Human abdominal and gluteal pre-adipocytes were differentiated into mature-like adipocytes in the presence of vehicle (DMSO), cholic acid (CA) or chenodeoxycholic acid (CDCA) (primary BAs, 50uM) for 12 days. Adipocyte differentiation was determined by qPCR and AdipoRed staining. Intracellular triglyceride accumulation, glucose concentration, and adipokine secretion were determined by ILab biochemistry analyser and ELISA. CDCA treatment of human abdominal and gluteal pre-adipocytes significantly impaired adipogenic differentiation, as demonstrated by AdipoRed staining. However, CA had no impact. Endorsing these data, intracellular triglyceride levels were significantly lower in CDCA-, but not CA-treated, mature-like adipocytes compared to vehicle-treated cells [vehicle: 2388±448.3 vs 126.1±25.41 nmol/mg protein, P=0.04]. In addition, intracellular glucose concentrations were elevated in CDCA-, but not CA-treated, cells compared to vehicle-treated ones (vehicle: 0.11±0.03 vs CDCA: 0.34±0.08 nmol/mg protein (n=3)]. Supporting these findings, expression of the key adipogenesis gene markers PPARG2, CEBPA, PLIN1 and ADIPOQ were significantly reduced in mature-like abdominal and gluteal cells following CDCA treatment, but were unchanged following CA treatment. Consistent with decreased ADIPOQ expression, cell media adiponectin levels were significantly lower in CDCA-treated cells. The effect of CA on adiponectin formation was not significant. In conclusion, we have demonstrated the differential effect of primary BAs on human adipocyte differentiation. Whilst CA had no effect, CDCA treatment resulted in marked repression of adipogenesis in human abdominal and gluteal adipocytes. Our data suggest that alterations in BA levels and/or composition of the BA pool can have a detrimental effect on adipogenesis, potentially contributing to abnormal lipid storage in non-adipose tissues, downstream leading to insulin resistance and hypertriglyceridemia. Additional studies are now required to elucidate the exact mechanisms through which BAs underpin their effects on adipose tissue function.