FXR activation normalizes insulin sensitivity in visceral preadipocytes of a rabbit model of MetS

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Abstract
Insulin resistance is the putative key underlying mechanism linking adipose tissue (AT) dysfunction with liver inflammation and steatosis in metabolic syndrome (MetS). We have recently demonstrated that the selective farnesoid X receptor (FXR) agonist obeticholic acid (OCA) ameliorates insulin resistance and the metabolic profile with a marked reduction in the amount of visceral AT (VAT) in a high-fat diet (HFD)-induced rabbit model of MetS. These effects were mediated by the activation of FXR, since treatment with the selective TGR5 agonist INT-777 was not able to ameliorate the metabolic parameters evaluated. Herein, we report the effects ofin vivoOCA dosing on the liver, the VAT, and the adipogenic capacity of VAT preadipocytes (rPADs) isolated from rabbits on a HFD compared with those on a control diet. VAT and liver were studied by immunohistochemistry, Western blot analysis, and RT-PCR. rPADs were exposed to a differentiating mixture to evaluate adipogenesis. Adipocyte size, hypoxia, and the expression of perilipin and cytosolic insulin-regulated glucose transporter GLUT4 (SLC2A4) were significantly increased in VAT isolated from the HFD rabbits, and normalized by OCA. The expression of steatosis and inflammation markers was increased in the liver of the HFD rabbits and normalized by OCA. rPADs isolated from the HFD rabbits were less sensitive to insulin, as demonstrated by the decreased insulin-induced glucose uptake, triglyceride synthesis, and adipogenic capacity, as well as by the impaired fusion of lipid droplets. OCA treatment preserved all the aforementioned metabolic functions. In conclusion, OCA dosing in a MetS rabbit model ameliorates liver and VAT functions. This could reflect the ability of OCA to restore insulin sensitivity in AT unable to finalize its storage function, counteracting MetS-induced metabolic alterations and pathological AT deposition.

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