Abstract
Stress of endoplasmic reticulum (ERS) is one of the molecular triggers of adipocyte dysfunction and chronic low inflammation accompanying obesity. ERS can be alleviated by chemical chaperones from the family of bile acids (BAs). Thus, two BAs currently used to treat cholestasis, ursodeoxycholic and tauroursodeoxycholic acid (UDCA and TUDCA), could potentially lessen adverse metabolic effects of obesity. Nevertheless, BAs effects on human adipose cells are mostly unknown. They could regulate gene expression through pathways different from their chaperone function, namely through activation of farnesoid X receptor (FXR) and TGR5, G-coupled receptor. Therefore, this study aimed to analyze effects of UDCA and TUDCA on human preadipocytes and differentiated adipocytes derived from paired samples of two distinct subcutaneous adipose tissue depots, abdominal and gluteal. While TUDCA did not alter proliferation of cells from either depot, UDCA exerted strong anti-proliferative effect. In differentiated adipocytes, acute exposition to neither TUDCA nor UDCA was able to reduce effect of ERS stressor tunicamycin. However, exposure of cells to UDCA during whole differentiation process decreased expression of ERS markers. At the same time however, UDCA profoundly inhibited adipogenic conversion of cells. UDCA abolished expression of PPARγ and lipogenic enzymes already in the early phases of adipogenesis. This anti-adipogenic effect of UDCA was not dependent on FXR or TGR5 activation, but could be related to ability of UDCA to sustain the activation of ERK1/2 previously linked with PPARγ inactivation. Finally, neither BAs did lower expression of chemokines inducible by TLR4 pathway, when UDCA enhanced their expression in gluteal adipocytes. Therefore while TUDCA has neutral effect on human preadipocytes and adipocytes, the therapeutic use of UDCA different from treating cholestatic diseases should be considered with caution because UDCA alters functions of human adipose cells.
Highlights
Obesity develops when the storage of surplus energy requires excessive expansion of the adipose tissue (AT)
Hypertrophy of adipocytes is connected with their dysfunction manifested by lower insulin sensitivity, higher basal lipolysis and altered production of cytokines contributing to a development of chronic low-grade inflammation [1,2]
Effect of bile acids (BAs) on proliferation of preadipocytes To evaluate effect of BAs on preadipocytes and adipocyte properties we have established the cultures of preadipocytes from paired samples of sAAT and sGAT of 10 obese women
Summary
Obesity develops when the storage of surplus energy requires excessive expansion of the adipose tissue (AT). Hypertrophy of adipocytes is connected with their dysfunction manifested by lower insulin sensitivity, higher basal lipolysis and altered production of cytokines contributing to a development of chronic low-grade inflammation [1,2]. ER is an organelle with the direct control over the cytokine production and lipid storage and its overload initiates processes that should enhance ER capacity and potentiate typical pro-inflammatory pathways [5]. The resolution of ERS by chemical chaperones has been shown to alleviate inflammation [5,8]. BAs were shown to prevent ERS in AT of obese mice [10]. Apart from their chaperone capacity, BAs may influence metabolic state of AT by regulating other pathways as evidenced by
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