Paradoxical resistance to high fat diet-induced obesity and altered macrophage polarization in mineralocorticoid receptor overexpressing mice.: MR overexpression and adipocyte differentiation

International audience: The mineralocorticoid receptor (MR) exerts pro-adipogenic and anti-thermogenic effects in vitro, yet its in vivo metabolic impact remains elusive. Wild type (WT) and transgenic (Tg) mice overexpressing human MR were subjected to standard chow (SC) or high fat diet (HFD) for 16 wks. Tg mice had a lower body weight gain than WT animals, and exhibited a relative resistance to HFD-induced obesity. This was associated with a decrease of fat mass, an increased population of smaller adipocytes, and an improved glucose tolerance compared to WT animals. Quantitative RT-PCR studies revealed decreased expression of PPARγ2, a master adipogenic gene, and of glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 1, consistent with an impaired local glucocorticoid signaling in adipose tissues (AT). This paradoxical resistance to HFD-induced obesity was not related to an adipogenesis defect since differentiation capacity of Tg preadipocytes isolated from stroma-vascular fractions was unaltered, suggesting that other non-adipocyte factors might compromise AT development. While AT macrophage infiltration was not different between genotypes, Tg mice exhibited a distinct macrophage polarization as revealed by FACS analysis and CD11c/CD206 expression studies. We further demonstrated that Tg macrophage-conditioned medium partially impaired preadipocyte differentiation. Therefore we propose that modification of M1/M2 polarization of hMR-overexpressing macrophages could account in part for the metabolic phenotype of Tg mice. Collectively, our results provide evidence that MR exerts a pivotal immunometabolic role by directly controlling adipocyte differentiation processes but also indirectly through macrophage polarization regulation. Our findings should be taken into account for the pharmacological treatment of metabolic disorders