Adipocyte-specific mineralocorticoid receptor deletion improves obesity-induced glucose intolerance in a sex-specific manner

Obesity is a state of overnutrition characterized by excess body fat and increased body mass index. The mineralocorticoid receptor (MR) is a ubiquitous nuclear receptor that is increased in visceral fat during obesity and mediates the metabolic effects of aldosterone and corticosterone. Fibroblast growth factor 21 (FGF21) is a hepatokine upregulated during fasting that enhances glucose handling via β-klotho co-receptor signaling. We hypothesize that deletion of the adipocyte mineralocorticoid receptor will improve glucose tolerance by increasing the actions of FGF21. We have developed a cre-activated inducible adipocyte-specific MR knock-out (MRKO) mouse model bred on a C57BL/J6 background to investigate the temporal effects of MR deletion on obesity in vivo. Five-week-old MRKO male and female mice, and MRflox control littermates, were placed on a high-fat diet (HFD, 60% kcal/fat). After 9 weeks, tamoxifen was administered (40mg/kg) to induce MR deletion. Body weight, body composition (EchoMRI), and oral glucose tolerance were assessed in HFD-fed mice before and 4 weeks after induction. Mice were euthanized after overnight fasting, plasma was collected and tissues flash frozen. RNA was extracted from gonadal white adipose tissue (gWAT), and insulin signaling and metabolism-related gene expression were assessed via qRT-PCR. Plasma aldosterone, FGF21, and insulin were measured via commercial ELISA kits. Across the span of the study, body weight and body composition were not significantly different between MRKO and MRflox mice of either sex. In male mice, glucose tolerance was similar before MR deletion (70529±4047 vs. 61737±5544 AUC, n=6, p=0.17), but it was improved only in MRKO mice (62688±4028 vs. 47520±1715; p=0.01). In addition, plasma levels of FGF21 were increased while insulin was reduced in MRKO mice, showing a significant negative correlation, but not in MRflox (R 2 = 0.91 vs. 0.08, respectively). Aldosterone levels were not influenced by MR deletion (550±143 vs. 627±24 pg/mL; p=0.60) or female (1010±91 vs. 947±145 pg/ml; p=0.73). MR deletion increased the expression of Insulin receptor (INSR) (1.03±0.12 vs 1.88±0.25 ddCT 2 ; p=0.02), insulin receptor substrate 1 (IRS-1) (1.04±0.16 vs. 1.89±0.27 ddCT 2 ; p=0.03), and glucose transporter type 4 (GLUT4) (1.23±0.37 vs 2.81±0.48 ddCT 2 ; p=0.03). Male MRKO mice also showed increased β-klotho expression in gWAT (1.19±0.34 vs 3.64±0.93 ddCT 2 ; p=0.04). Conversely, MR deletion did not influence body adiposity, glucose homeostasis, or gWAT gene expression in obese female mice. In conclusion, we identified a pivotal role of β-klotho in increasing insulin-regulating genes and improving glucose tolerance in obese male mice. Thus, this study is the first to report that adipose tissue MR could negatively regulate β-klotho expression in a sex-specific manner, impairing glucose homeostasis by reducing FGF21-dependent insulin signaling. HL135158 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.