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. 2026 Jan;28(1):562-573.
doi: 10.1111/dom.70230. Epub 2025 Oct 28.

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

Meghan Blair Turner  1 , Helen-Rose Pangilinan  1 , Sehyung Park  2 , Botshelo Angoma  1 , Robert N Helsley  2 , Analia S Loria  1
Affiliations

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

Meghan Blair Turner et al. Diabetes Obes Metab. 2026 Jan.

Abstract

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 (AdipoMRKO) 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 (AdipoMRfl) 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 AdipoMRKO 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 AdipoMRfl 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.

Keywords: adipocyte; glucose homeostasis; mineralocorticoid receptor; sex differences.

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