Liver and visceral ectopic fatty tissue disposition is a major metabolic derangement leading to type 2 diabetes, hypertension, dyslipidaemia, recapitulated in the metabolic syndrome (MetS). We have demonstrated that the selective FXR agonist obeticholic acid (OCA, INT-747) ameliorates the metabolic profile and reduces visceral adipose tissue (VAT) in a high-fat diet (HFD)-induced rabbit model of MetS. We now report the effects of OCA treatment in HFD (0.5% cholesterol and 4% peanut oil) rabbits, and on the adipogenic capacity of isolated VAT rabbit preadipocytes (rPAD). VAT and liver were studied by immunohistochemistry, Western blot and RT-PCR. Isolated rPAD were exposed to adipocyte differentiating mixture (DIM) to evaluate their adipogenic ability. Adipocyte size, as well as expression of the anti-lipolytic protein perilipin-1 and cytosolic GLUT-4, indicating adipocyte dysfunction, were significantly increased in VAT of HFD compared to regular diet (RD) rabbits, and normalized by OCA treatment. TNFα expression, along with other steatosis (PPARγ and adiponectin) and inflammation (TNFα, IL6 and IL10) markers were also significantly increased in HFD liver and normalized by OCA treatment. Interestingly, rPAD from HFD-rabbits showed a reduced responsiveness to DIM, and in particular to insulin, as demonstrated by reduced triglyceride synthesis, decreased glucose uptake, and impaired lipid droplets fusion, as well as by the reduced induction of adipogenesis- and lipid droplet-handling specific genes. OCA treatment preserved all the DIM-induced adipocyte functions, normalizing the markedly increased lipid droplet size in HFD-derived adipocytes and the increased major lipid-fusion complex SNARE. In conclusion, OCA dosing in a MetS rabbit model positively affects liver and VAT functions, increasing their efficiency in triglyceride and lipid droplet handling. This could reflect the ability of OCA to restore insulin sensitivity in committed adipose tissue unable to finalize its storage function, thus counteracting MetS-induced metabolic alterations and pathological fatty tissue disposition.
27 Apr - 01 May 2013
European Society of Endocrinology