Adipocyte‐specific deletion of the mineralocorticoid receptor improves glucose homeostasis and associates with FGF21 ‐adiponectin signalling in obese male mice
Year: 2025
Type: article
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 (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.
Source: Diabetes Obesity and Metabolism
DOI: 10.1111/dom.70230
Authors: Meghan Blair Turner, Helen‐Rose Pangilinan, Sehyung Park, Botshelo Angoma, Robert N. Helsley, Analia S. Loria
Institution: University of Kentucky
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Center of Research on Obesity and Cardiovascular Diseases, Identification of Carnitine Palmitoyltransferase 1a (CPT1a) as a Novel Regulator of Lipoprotein Metabolism, Effect of early life stress on obesity-induced hypertension in mice, Center of Research on Obesity and Cardiovascular Disease, G7708946113, G848489246, Deciphering the Mechanisms by which Long Chain Fatty Acid Oxidation Influences Spatial Microvesicular Steatosis
OpenAlex ID: W4415647851