Adipocyte-specific deletion of the mineralocorticoid receptor improves glucose homeostasis and associates with FGF21-adiponectin signalling in obese male mice

Aims: The mineralocorticoid receptor (MR) is a ubiquitous nuclear receptor that is increased during obesity. Fibroblast growth factor 21 (FGF-21) is a hepatokine that enhances glucose metabolism by binding and activating fibroblast growth factor receptors in complex with the beta-klotho co-receptor (β-klotho). This study tested the hypothesis that adipocyte MR contributes to the development of glucose intolerance in obesity settings by impairing FGF-21-mediated glucose handling in adipose tissue. Materials and Methods: An adipocyte-specific inducible MR knockout (AdipoMR^KO) mouse model was generated to investigate metabolic effects during obesity. Tamoxifen-induced MR deletion was performed in 14-week-old male and female mice after 9 weeks on a high-fat diet (HFD). MR floxed (AdipoMR^fl) mice served as control littermates. Body weight, body composition, oral glucose tolerance, insulin tolerance, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and adipokines were measured 4 weeks post-treatment. Results: Body weight and composition were not significantly different before or after MR deletion in mice of either sex. In HFD-fed male AdipoMR^KO mice, glucose tolerance and HOMA-IR were improved, while insulin-sensitising genes including β-klotho were increased in perigonadal white adipose tissue (gWAT) compared with AdipoMR^fl mice. Notably, adipocyte MR deletion increased plasma FGF-21, which was associated with increased FGF-21 and adiponectin protein expression in gWAT. Conversely, MR deletion in HFD-fed female mice did not influence body adiposity, glucose homeostasis, or gWAT gene expression. Conclusions: Deletion of the adipocyte MR activates the FGF-21/β-klotho/adiponectin axis in obese male mice only. Thus, these data indicate that the dysfunctional FGF-21/β-klotho/adiponectin axis is associated with impaired glucose handling in a sex-specific manner.